In 2016, the U.S. Food and Drug Administration approved nusinersen, the first treatment for spinal muscular atrophy (SMA). Until then, SMA had a mortality rate nearly double that of the general population.¹ Two-thirds of patients were symptomatic within 6 months of birth and, in the absence of mechanical ventilation and other support, had a nearly 100% mortality rate by age 2.²

Five years later, there are three approved treatments for SMA, all of which have been shown to slow or even halt disease progression in many patients. These new therapies, coupled with expanded newborn screening and advancements in optimizing patient care, are changing the natural history of the disease and offering a prognosis that extends well beyond adolescence. Neurologists, whose SMA patient population once consisted almost entirely of children, are now treating more adults with the disease. Indeed, more than half of all people alive with SMA in the United States today are adults, according to Cure SMA.

“Managing SMA used to be clinic follow-ups where we were doing our best supportive care and watching people fall apart before our eyes,” said John Brandsema, MD, a physician and neuromuscular section head at the Children’s Hospital of Philadelphia. “Today, what we see in the vast majority of people is that they are either the same as they were before – which is completely against the natural history of this disease and something to be celebrated – or that people are really better with their function. It totally changes everything in the clinic.”

Among those changes are a more proactive approach to rehabilitation and an even greater emphasis on personalized medicine and multidisciplinary care. But there is also a need for updated treatment guidelines, a new classification system to measure disease severity, specific biomarkers to guide therapy choices, more data on long-term efficacy of existing therapeutics, new medications to complement those therapies, and a deeper understanding of a disease that may have treatment options but still has no cure.
 

Advances in early diagnosis

Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which provides instructions for producing a protein called SMN that is critical for the maintenance and function of motor neurons. Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe. SMA is rare, affecting about 1 in 10,000 newborns.

In approximately 96% of patients, SMA is caused by homozygous loss of the SMN1 gene. People with SMA have at least one copy of the SMN2 gene, sometimes called a “backup” gene, that also produces SMN protein. However, a single nucleotide difference between SMN2 and SMN1 causes about 90% of the protein produced by SMN2 to be truncated and less stable. Even with multiple copies of SMN2 present, as is the case with many infants with SMA, the amount of functional protein produced isn’t enough to compensate for the loss of SMN1.³

All three approved medications are SMN up-regulators and work to increase the amount of functional SMN protein. Starting these medications early, even before symptoms present, is critical to preserve motor function. Early treatment depends on early diagnosis, which became more widespread after 2018 when SMA was added to the federally Recommended Uniform Screening Panel for newborns. As of July 1, 2022, 47 states have incorporated SMA newborn screening into their state panel, ensuring that 97% of all infants born in the United States undergo SMA screening shortly after birth. Screening in the remaining states – Hawaii, Nevada, and South Carolina – and Washington, D.C. is expected by mid-2023.

SMA newborn screening is a PCR-based assay that detects homozygous SMN1 gene deletion found in about 95% of all people with SMA. The remaining 5% of cases are caused by various genetic mutations that can only be detected with gene sequencing. In these cases, and in children who don’t undergo SMA newborn screening, the disease is usually identified when symptoms are noticed by a parent, pediatrician, or primary care provider. But a study found that in 2018 only 52.7% of pediatricians correctly identified genetic testing as a requirement for a definitive diagnosis of SMA; in 2019, with a larger sample size, that number decreased to 45%.⁴ The lack of awareness of diagnostic requirements for SMA could contribute to delays in diagnosis, said Mary Schroth, MD, chief medical officer for Cure SMA and a coauthor of the study.

“In our world, suspicion of SMA in an infant is an emergency situation,” Dr. Schroth said. “These babies need to be referred immediately and have genetic testing so that treatment can begin as soon as possible.”

Based on the study findings, Dr. Schroth and others with Cure SMA launched a new tool in 2021 designed to help pediatricians, primary care physicians, and parents identify early signs of SMA, so that a referral to a pediatric neurologist happens quickly. Called SMArt Moves, the educational resource features videos and a checklist to help increase early detection in infants who had a negative SMA newborn screening result or did not receive SMA screening at birth.⁵
 

Who to treat, when, and with which treatment

For many patients, having multiple effective treatment options means that SMA is no longer a fatal disease in early childhood, but one that can be managed into adolescence and adulthood. The question for clinicians is, who do they treat, when, and with which treatment?

Studies have long shown that the number of copies of the backup gene that a patient has is inversely associated with disease severity.⁶ In 2018, a group of SMA experts published a treatment algorithm to help guide decision-making following a positive SMA newborn screening.⁷ The treatment guidelines were updated in 2020 based on clinical trial data for presymptomatic infants, and current recommendations include immediate treatment for infants with two to four copies of the SMN2 gene.⁸ For patients with only one copy of SMN2, most of whom will likely be symptomatic at birth, the guidelines recommend that treatment decisions be made jointly between the clinician and the family.^7,8

Some suggest that the number of SMN2 copies a patient has should also be a factor in determining phenotype, which has started a conversation on the development of a new classification system.⁹ The original classification system for disease severity – Types 0-4 – was based on age of onset and degree of motor function achieved, with Type 0 developing prenatally and being the most severe and Type 4 developing in adulthood. Type 1 is the most common, affecting more than half of all people with SMA, followed by Types 2-4. In 2018, updated consensus care guidelines offered a revised classification system that better reflected disease progression in the age of therapy. The functional motor outcomes include nonsitters (historically Type I), sitters (historically Type 2/3), and walkers (historically Type 3/4).^10,11 These guidelines are a start, but clinicians say more revision is needed.

“Types 1, 2, 3, 4 were based on function – getting to a certain point and then losing it, but now that we can treat this disease, people will shift categories based on therapeutic response or based on normal development that is possible now that the neurologic piece has been stabilized,” Dr. Brandsema said. “We need to completely change our thinking around all these different aspects of SMA management.”

While discussions of a new classification system for SMA are underway, another effort to update treatment recommendations is closer to completion. Led by Cure SMA, a group of about 50 physician experts in the United States and Europe who specialize in SMA are revising guidelines for diagnosis and treatment, the first time the recommendations have been updated since 2018. The updated recommendations, which should be published later this year, will focus on diagnosis and treatment considerations.

“We have three treatments that are available, and there are specific FDA indications for each of those, but it’s not totally clear just how those medications should be used or applied to different clinical situations,” said Dr. Schroth. “We’re in a rapid phase of learning right now in the SMA community, trying to understand how these treatments alter physiology and disease outcomes and how to best use the tools that we now have available to us. In parallel with clinical treatments, we have to be doing the best care we can to optimize the outcomes for those treatments.”
 

Research advances in 2021

Although all three drugs approved to treat SMA – nusinersen (Spinraza; Biogen), onasemnogene abeparvovec-xioi gene replacement therapy (Zolgensma; Novartis Gene Therapies), and risdiplam (Evrysdi, Genentech/Roche) – are highly effective, there are still unanswered questions and unmet needs. New research findings from 2021 focused on higher dosing, different drug-delivery methods, combination therapy, and complementary therapeutics to address SMA comorbidities.

Higher-dose nusinersen. The first drug approved to treat SMA, nusinersen is an antisense oligonucleotide approved for all ages and all SMA types. It works by altering splicing of the SMN2 gene pre-mRNA to make more complete SMN protein. Given as an intrathecal (IT) injection, four “loading doses” are administered within the first 2 months of treatment, followed by a maintenance dose every 4 months for the duration of the individual’s life.

Reports from patients of waning effects of nusinersen just prior to follow-up treatment have led some clinicians to ask if a higher dose may be needed. A study underway seeks to address that issue.

DEVOTE is a phase 2/3 trial to study the safety and efficacy of high-dose nusinersen in patients with SMA. Preliminary findings reported in 2021 found no adverse events among patients treated with 28 mg of nusinersen for 161-257 days.¹² Another analysis from this trial found that higher doses are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with SMA and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.¹³ The trial is ongoing.

Another trial, ASCEND, is a phase 3B study assessing higher dose nusinersen in patients previously treated with risdiplam. Recruitment for that trial began in October 2021.

Long-term efficacy and IT administration of SMA therapy. Several studies are looking at the long-term efficacy and alternate routes of administration of onasemnogene abeparvovec and other SMA therapies.

A one-time gene replacement therapy delivered via an IV infusion replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene. FDA approved in 2019, it is authorized for use in patients with SMA up to 2 years of age.

The latest data from an ongoing, long-term follow-up safety study of onasemnogene abeparvovec, published in May 2021, suggest that the treatment’s effects persist more than 5 years after treatment. Researchers followed 13 infants with symptomatic SMA type 1 since the beginning of the phase 1 clinical trial of the gene transfer therapy. All patients who received the therapeutic dose maintained their baseline motor function, and two of the patients actually improved without other SMN-targeted treatment. At a median 6.2 years after they received treatment, all were alive and none needed permanent ventilation.¹⁴

After a 2-year hold by the FDA, a study of IT administration of onasemnogene abeparvovec is now enrolling patients. Citing concerns from animal studies that IT administration might result in dorsal root ganglia injury, the FDA issued a partial hold on the STRONG trial in 2019. Following positive study results in nonhuman primates, the FDA announced the trial can continue. Novartis is launching a new phase 3 STEER trial to test the drug delivered intrathecally in patients aged 2-18 years with Type 2 SMA. IT administration could allow the gene therapy to be used safely and effectively in more patients with SMA.

Efficacy of risdiplam in more patients. The first oral treatment for SMA was approved by the FDA in 2020. It’s given once per day in patients with SMA of all ages and disease types. The drug increases functional SMN protein production by the SMN2 gene.

A July 2021 publication of the results of the FIREFISH study found that infants with Type I SMA treated with risdiplam for 12 months were significantly more likely to achieve motor milestones, such as sitting without support, compared with untreated infants with Type 1 SMA.¹⁵ Risdiplam is also effective in older patients with Type 2 or 3 SMA, according to results published in December from the SUNFISH clinical trial.¹⁶ Another study, RAINBOWFISH, is studying safety and efficacy at 24 months in presymptomatic infants started on treatment at up to 6 weeks of age.

The efficacy of risdiplam in previously treated patients is the subject of JEWELFISH, an ongoing study in patients 6 months to 60 years with SMA. Preliminary data presented at the 2020 Virtual SMA Research and Clinical Care Meeting suggest treatment with risdiplam led to a median two-fold increase in the amount of blood SMN protein levels after 4 weeks, which was sustained for at least 24 months.¹⁷

Combination therapy. Among the more eagerly awaited results are those from studies of combination therapies, including those that combine approved SMN up-regulators with new non–SMN-targeted therapeutics.

“We’re seeing that while these three approved therapies have dramatic results, especially for infants who are treated presymptomatically, there are still unmet medical needs in those patients, particularly for older teens and adults whose disease may have progressed before they were able to start therapy,” said Jackie Glascock, PhD, vice president of research for Cure SMA.

Of particular interest are studies of myostatin inhibitors, therapeutics that block the production of the protein myostatin. Myostatin acts on muscle cells to reduce muscle growth. Animal studies suggest that inhibiting myostatin increases muscle mass, which could be important in patients with muscle loss due to SMA.

Three experimental myostatin inhibitors are currently in clinical trials. MANATEE is a global phase 2-3 trial that aims to evaluate the safety and efficacy of the antimyostatin antibody GYM329 (RO7204239) in combination with risdiplam. SAPPHIRE is a phase 3 trial of apitegromab (SRK-015) in combination with nusinersen or risdiplam. RESILIANT is a phase 3 trial of tadefgrobep alfa in combination with other treatments.

A trial is underway to study the efficacy and safety of nusinersen in patients with persistent symptoms of SMA after treatment with the gene therapy. The phase 4 study, RESPOND, is enrolling children aged 2-36 months.

What’s needed next

Despite the advances in treatment and patient care, Dr. Brandsema, Dr. Schroth, and Dr. Glascock note that there remain unmet needs in the SMA community in a variety of areas.

Increased focus on adults with SMA. Before nusinersen, treatment of SMA mainly involved treating its symptoms. Many patients stopped seeing their neurologist, relying more heavily on pulmonary care specialists and/or primary care providers to address breathing, nutrition, and mobility problems. “Now with the approval of these treatments, they’re coming back to see their neurologists and are becoming more visible in the SMA community,” Dr. Schroth said.

Despite this re-emergence, a 2020 meta-analysis of studies on adults with SMA found a paucity of data on physical and occupational therapy, respiratory management, mental health care, and palliative care.¹⁸

“There is just so much work we need to do in the area of adult clinical care of SMA.”

Treatment algorithms. While the development of the newborn screening algorithm and revised patient care guidelines are helpful resources, clinicians still face uncertainty when choosing which therapy will work best for their patients. Treatment algorithms that help clinicians figure out what therapy or combination of therapies will offer the best outcomes for individual patients are desperately needed, Dr. Brandsema said.

“Each person’s experience of this disease is so unique to the individual based partly on their genetics and partly on the factors about what got them into care and how compliant they are with everything we’re trying to do to help them,” he said. “Biomarkers would help clinicians create personalized treatment plans for each patient.”

More basic science. While scientists have a good understanding of the SMN gene, there are many unanswered questions about the function of the SMN protein and its relationship to motor neuron loss. SMN is a ubiquitously expressed protein, and its function in other cell types is largely unknown. Despite all of the research advances, there is much basic science left to be done.

“We are strongly advocating to regulatory authorities that these aren’t cures and we need to continue to invest in the basic research,” Dr. Glascock said. “These biological questions that pertain to SMN and its function and expression really drive drug development. I really think that understanding those pathways better will lead us to more druggable targets.”
 

Two deaths from liver failure linked to spinal muscular atrophy drug

Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug’s manufacturer.

The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.

These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.

“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.

“While this is important safety information, it is not a new safety signal,” it adds.
 

Rare genetic disorder

SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.

Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.

Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.

The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.

“We have notified health authorities in all markets where Zolgensma is used, including the FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.

Studies have suggested that the treatment’s effects persist more than 5 years after infusion.

Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.

The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.

That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.

None of the current trials will be affected by the two deaths reported, according to a Novartis spokesperson.
 

Kelli Whitlock Burton is a staff writer/reporter for Medscape Neurology and MDedge Neurology.

References

1. Viscidi E et al. Comparative all-cause mortality among a large population of patients with spinal muscular atrophy versus matched controls. Neurol Ther. 2022 Mar;11(1):449-457. doi: 10.1007/s40120-021-00307-7.

2. Finkel RS et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-817. doi: 10.1212/WNL.0000000000000741.

3. Klotz J et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021 Sep;236:13-20.e1. doi: 10.1016/j.jpeds.2021.06.033.

4. Curry M et al. Awareness screening and referral patterns among pediatricians in the United States related to early clinical features of spinal muscular atrophy (SMA). BMC Pediatr. 2021 May;21(1):236. doi: 10.1186/s12887-021-02692-2.

5. SMArt Moves. https://smartmoves.curesma.org/

6. Swoboda KJ et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.

7. Glascock J et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145-158. doi: 10.3233/JND-180304.

8. Glascock J et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi: 10.3233/JND-190468.

9. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52.

10. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi: 10.1016/j.nmd.2017.11.005.

11. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.

12. Pascual SI et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021, Mar 15-18.

13. Finkel RS et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting, Jun 9-11. Abstract P46.

14. Mendell JR et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021 Jul;78(7):834-841. doi: 10.1001/jamaneurol.2021.1272.

15. Darras BT et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.

16. Mercuri E et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum in: Lancet Neurol. 2022 Feb;21(2):e2. doi: 10.1016/S1474-4422(22)00006-0. Correction in: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00038-2.

17. Genentech announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with SMA. https://www.curesma.org/genentech-risdiplam-data-conference-2020/

18. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. doi: 10.1186/s13023-020-1339-3.




 

In 2016, the U.S. Food and Drug Administration approved nusinersen, the first treatment for spinal muscular atrophy (SMA). Until then, SMA had a mortality rate nearly double that of the general population.¹ Two-thirds of patients were symptomatic within 6 months of birth and, in the absence of mechanical ventilation and other support, had a nearly 100% mortality rate by age 2.²

Five years later, there are three approved treatments for SMA, all of which have been shown to slow or even halt disease progression in many patients. These new therapies, coupled with expanded newborn screening and advancements in optimizing patient care, are changing the natural history of the disease and offering a prognosis that extends well beyond adolescence. Neurologists, whose SMA patient population once consisted almost entirely of children, are now treating more adults with the disease. Indeed, more than half of all people alive with SMA in the United States today are adults, according to Cure SMA.

“Managing SMA used to be clinic follow-ups where we were doing our best supportive care and watching people fall apart before our eyes,” said John Brandsema, MD, a physician and neuromuscular section head at the Children’s Hospital of Philadelphia. “Today, what we see in the vast majority of people is that they are either the same as they were before – which is completely against the natural history of this disease and something to be celebrated – or that people are really better with their function. It totally changes everything in the clinic.”

Among those changes are a more proactive approach to rehabilitation and an even greater emphasis on personalized medicine and multidisciplinary care. But there is also a need for updated treatment guidelines, a new classification system to measure disease severity, specific biomarkers to guide therapy choices, more data on long-term efficacy of existing therapeutics, new medications to complement those therapies, and a deeper understanding of a disease that may have treatment options but still has no cure.
 

Advances in early diagnosis

Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which provides instructions for producing a protein called SMN that is critical for the maintenance and function of motor neurons. Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe. SMA is rare, affecting about 1 in 10,000 newborns.

In approximately 96% of patients, SMA is caused by homozygous loss of the SMN1 gene. People with SMA have at least one copy of the SMN2 gene, sometimes called a “backup” gene, that also produces SMN protein. However, a single nucleotide difference between SMN2 and SMN1 causes about 90% of the protein produced by SMN2 to be truncated and less stable. Even with multiple copies of SMN2 present, as is the case with many infants with SMA, the amount of functional protein produced isn’t enough to compensate for the loss of SMN1.³

All three approved medications are SMN up-regulators and work to increase the amount of functional SMN protein. Starting these medications early, even before symptoms present, is critical to preserve motor function. Early treatment depends on early diagnosis, which became more widespread after 2018 when SMA was added to the federally Recommended Uniform Screening Panel for newborns. As of July 1, 2022, 47 states have incorporated SMA newborn screening into their state panel, ensuring that 97% of all infants born in the United States undergo SMA screening shortly after birth. Screening in the remaining states – Hawaii, Nevada, and South Carolina – and Washington, D.C. is expected by mid-2023.

SMA newborn screening is a PCR-based assay that detects homozygous SMN1 gene deletion found in about 95% of all people with SMA. The remaining 5% of cases are caused by various genetic mutations that can only be detected with gene sequencing. In these cases, and in children who don’t undergo SMA newborn screening, the disease is usually identified when symptoms are noticed by a parent, pediatrician, or primary care provider. But a study found that in 2018 only 52.7% of pediatricians correctly identified genetic testing as a requirement for a definitive diagnosis of SMA; in 2019, with a larger sample size, that number decreased to 45%.⁴ The lack of awareness of diagnostic requirements for SMA could contribute to delays in diagnosis, said Mary Schroth, MD, chief medical officer for Cure SMA and a coauthor of the study.

“In our world, suspicion of SMA in an infant is an emergency situation,” Dr. Schroth said. “These babies need to be referred immediately and have genetic testing so that treatment can begin as soon as possible.”

Based on the study findings, Dr. Schroth and others with Cure SMA launched a new tool in 2021 designed to help pediatricians, primary care physicians, and parents identify early signs of SMA, so that a referral to a pediatric neurologist happens quickly. Called SMArt Moves, the educational resource features videos and a checklist to help increase early detection in infants who had a negative SMA newborn screening result or did not receive SMA screening at birth.⁵
 

Who to treat, when, and with which treatment

For many patients, having multiple effective treatment options means that SMA is no longer a fatal disease in early childhood, but one that can be managed into adolescence and adulthood. The question for clinicians is, who do they treat, when, and with which treatment?

Studies have long shown that the number of copies of the backup gene that a patient has is inversely associated with disease severity.⁶ In 2018, a group of SMA experts published a treatment algorithm to help guide decision-making following a positive SMA newborn screening.⁷ The treatment guidelines were updated in 2020 based on clinical trial data for presymptomatic infants, and current recommendations include immediate treatment for infants with two to four copies of the SMN2 gene.⁸ For patients with only one copy of SMN2, most of whom will likely be symptomatic at birth, the guidelines recommend that treatment decisions be made jointly between the clinician and the family.^7,8

Some suggest that the number of SMN2 copies a patient has should also be a factor in determining phenotype, which has started a conversation on the development of a new classification system.⁹ The original classification system for disease severity – Types 0-4 – was based on age of onset and degree of motor function achieved, with Type 0 developing prenatally and being the most severe and Type 4 developing in adulthood. Type 1 is the most common, affecting more than half of all people with SMA, followed by Types 2-4. In 2018, updated consensus care guidelines offered a revised classification system that better reflected disease progression in the age of therapy. The functional motor outcomes include nonsitters (historically Type I), sitters (historically Type 2/3), and walkers (historically Type 3/4).^10,11 These guidelines are a start, but clinicians say more revision is needed.

“Types 1, 2, 3, 4 were based on function – getting to a certain point and then losing it, but now that we can treat this disease, people will shift categories based on therapeutic response or based on normal development that is possible now that the neurologic piece has been stabilized,” Dr. Brandsema said. “We need to completely change our thinking around all these different aspects of SMA management.”

While discussions of a new classification system for SMA are underway, another effort to update treatment recommendations is closer to completion. Led by Cure SMA, a group of about 50 physician experts in the United States and Europe who specialize in SMA are revising guidelines for diagnosis and treatment, the first time the recommendations have been updated since 2018. The updated recommendations, which should be published later this year, will focus on diagnosis and treatment considerations.

“We have three treatments that are available, and there are specific FDA indications for each of those, but it’s not totally clear just how those medications should be used or applied to different clinical situations,” said Dr. Schroth. “We’re in a rapid phase of learning right now in the SMA community, trying to understand how these treatments alter physiology and disease outcomes and how to best use the tools that we now have available to us. In parallel with clinical treatments, we have to be doing the best care we can to optimize the outcomes for those treatments.”
 

Research advances in 2021

Although all three drugs approved to treat SMA – nusinersen (Spinraza; Biogen), onasemnogene abeparvovec-xioi gene replacement therapy (Zolgensma; Novartis Gene Therapies), and risdiplam (Evrysdi, Genentech/Roche) – are highly effective, there are still unanswered questions and unmet needs. New research findings from 2021 focused on higher dosing, different drug-delivery methods, combination therapy, and complementary therapeutics to address SMA comorbidities.

Higher-dose nusinersen. The first drug approved to treat SMA, nusinersen is an antisense oligonucleotide approved for all ages and all SMA types. It works by altering splicing of the SMN2 gene pre-mRNA to make more complete SMN protein. Given as an intrathecal (IT) injection, four “loading doses” are administered within the first 2 months of treatment, followed by a maintenance dose every 4 months for the duration of the individual’s life.

Reports from patients of waning effects of nusinersen just prior to follow-up treatment have led some clinicians to ask if a higher dose may be needed. A study underway seeks to address that issue.

DEVOTE is a phase 2/3 trial to study the safety and efficacy of high-dose nusinersen in patients with SMA. Preliminary findings reported in 2021 found no adverse events among patients treated with 28 mg of nusinersen for 161-257 days.¹² Another analysis from this trial found that higher doses are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with SMA and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.¹³ The trial is ongoing.

Another trial, ASCEND, is a phase 3B study assessing higher dose nusinersen in patients previously treated with risdiplam. Recruitment for that trial began in October 2021.

Long-term efficacy and IT administration of SMA therapy. Several studies are looking at the long-term efficacy and alternate routes of administration of onasemnogene abeparvovec and other SMA therapies.

A one-time gene replacement therapy delivered via an IV infusion replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene. FDA approved in 2019, it is authorized for use in patients with SMA up to 2 years of age.

The latest data from an ongoing, long-term follow-up safety study of onasemnogene abeparvovec, published in May 2021, suggest that the treatment’s effects persist more than 5 years after treatment. Researchers followed 13 infants with symptomatic SMA type 1 since the beginning of the phase 1 clinical trial of the gene transfer therapy. All patients who received the therapeutic dose maintained their baseline motor function, and two of the patients actually improved without other SMN-targeted treatment. At a median 6.2 years after they received treatment, all were alive and none needed permanent ventilation.¹⁴

After a 2-year hold by the FDA, a study of IT administration of onasemnogene abeparvovec is now enrolling patients. Citing concerns from animal studies that IT administration might result in dorsal root ganglia injury, the FDA issued a partial hold on the STRONG trial in 2019. Following positive study results in nonhuman primates, the FDA announced the trial can continue. Novartis is launching a new phase 3 STEER trial to test the drug delivered intrathecally in patients aged 2-18 years with Type 2 SMA. IT administration could allow the gene therapy to be used safely and effectively in more patients with SMA.

Efficacy of risdiplam in more patients. The first oral treatment for SMA was approved by the FDA in 2020. It’s given once per day in patients with SMA of all ages and disease types. The drug increases functional SMN protein production by the SMN2 gene.

A July 2021 publication of the results of the FIREFISH study found that infants with Type I SMA treated with risdiplam for 12 months were significantly more likely to achieve motor milestones, such as sitting without support, compared with untreated infants with Type 1 SMA.¹⁵ Risdiplam is also effective in older patients with Type 2 or 3 SMA, according to results published in December from the SUNFISH clinical trial.¹⁶ Another study, RAINBOWFISH, is studying safety and efficacy at 24 months in presymptomatic infants started on treatment at up to 6 weeks of age.

The efficacy of risdiplam in previously treated patients is the subject of JEWELFISH, an ongoing study in patients 6 months to 60 years with SMA. Preliminary data presented at the 2020 Virtual SMA Research and Clinical Care Meeting suggest treatment with risdiplam led to a median two-fold increase in the amount of blood SMN protein levels after 4 weeks, which was sustained for at least 24 months.¹⁷

Combination therapy. Among the more eagerly awaited results are those from studies of combination therapies, including those that combine approved SMN up-regulators with new non–SMN-targeted therapeutics.

“We’re seeing that while these three approved therapies have dramatic results, especially for infants who are treated presymptomatically, there are still unmet medical needs in those patients, particularly for older teens and adults whose disease may have progressed before they were able to start therapy,” said Jackie Glascock, PhD, vice president of research for Cure SMA.

Of particular interest are studies of myostatin inhibitors, therapeutics that block the production of the protein myostatin. Myostatin acts on muscle cells to reduce muscle growth. Animal studies suggest that inhibiting myostatin increases muscle mass, which could be important in patients with muscle loss due to SMA.

Three experimental myostatin inhibitors are currently in clinical trials. MANATEE is a global phase 2-3 trial that aims to evaluate the safety and efficacy of the antimyostatin antibody GYM329 (RO7204239) in combination with risdiplam. SAPPHIRE is a phase 3 trial of apitegromab (SRK-015) in combination with nusinersen or risdiplam. RESILIANT is a phase 3 trial of tadefgrobep alfa in combination with other treatments.

A trial is underway to study the efficacy and safety of nusinersen in patients with persistent symptoms of SMA after treatment with the gene therapy. The phase 4 study, RESPOND, is enrolling children aged 2-36 months.

What’s needed next

Despite the advances in treatment and patient care, Dr. Brandsema, Dr. Schroth, and Dr. Glascock note that there remain unmet needs in the SMA community in a variety of areas.

Increased focus on adults with SMA. Before nusinersen, treatment of SMA mainly involved treating its symptoms. Many patients stopped seeing their neurologist, relying more heavily on pulmonary care specialists and/or primary care providers to address breathing, nutrition, and mobility problems. “Now with the approval of these treatments, they’re coming back to see their neurologists and are becoming more visible in the SMA community,” Dr. Schroth said.

Despite this re-emergence, a 2020 meta-analysis of studies on adults with SMA found a paucity of data on physical and occupational therapy, respiratory management, mental health care, and palliative care.¹⁸

“There is just so much work we need to do in the area of adult clinical care of SMA.”

Treatment algorithms. While the development of the newborn screening algorithm and revised patient care guidelines are helpful resources, clinicians still face uncertainty when choosing which therapy will work best for their patients. Treatment algorithms that help clinicians figure out what therapy or combination of therapies will offer the best outcomes for individual patients are desperately needed, Dr. Brandsema said.

“Each person’s experience of this disease is so unique to the individual based partly on their genetics and partly on the factors about what got them into care and how compliant they are with everything we’re trying to do to help them,” he said. “Biomarkers would help clinicians create personalized treatment plans for each patient.”

More basic science. While scientists have a good understanding of the SMN gene, there are many unanswered questions about the function of the SMN protein and its relationship to motor neuron loss. SMN is a ubiquitously expressed protein, and its function in other cell types is largely unknown. Despite all of the research advances, there is much basic science left to be done.

“We are strongly advocating to regulatory authorities that these aren’t cures and we need to continue to invest in the basic research,” Dr. Glascock said. “These biological questions that pertain to SMN and its function and expression really drive drug development. I really think that understanding those pathways better will lead us to more druggable targets.”
 

Two deaths from liver failure linked to spinal muscular atrophy drug

Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug’s manufacturer.

The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.

These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.

“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.

“While this is important safety information, it is not a new safety signal,” it adds.
 

Rare genetic disorder

SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.

Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.

Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.

The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.

“We have notified health authorities in all markets where Zolgensma is used, including the FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.

Studies have suggested that the treatment’s effects persist more than 5 years after infusion.

Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.

The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.

That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.

None of the current trials will be affected by the two deaths reported, according to a Novartis spokesperson.
 

Kelli Whitlock Burton is a staff writer/reporter for Medscape Neurology and MDedge Neurology.

References

1. Viscidi E et al. Comparative all-cause mortality among a large population of patients with spinal muscular atrophy versus matched controls. Neurol Ther. 2022 Mar;11(1):449-457. doi: 10.1007/s40120-021-00307-7.

2. Finkel RS et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-817. doi: 10.1212/WNL.0000000000000741.

3. Klotz J et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021 Sep;236:13-20.e1. doi: 10.1016/j.jpeds.2021.06.033.

4. Curry M et al. Awareness screening and referral patterns among pediatricians in the United States related to early clinical features of spinal muscular atrophy (SMA). BMC Pediatr. 2021 May;21(1):236. doi: 10.1186/s12887-021-02692-2.

5. SMArt Moves. https://smartmoves.curesma.org/

6. Swoboda KJ et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.

7. Glascock J et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145-158. doi: 10.3233/JND-180304.

8. Glascock J et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi: 10.3233/JND-190468.

9. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52.

10. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi: 10.1016/j.nmd.2017.11.005.

11. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.

12. Pascual SI et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021, Mar 15-18.

13. Finkel RS et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting, Jun 9-11. Abstract P46.

14. Mendell JR et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021 Jul;78(7):834-841. doi: 10.1001/jamaneurol.2021.1272.

15. Darras BT et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.

16. Mercuri E et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum in: Lancet Neurol. 2022 Feb;21(2):e2. doi: 10.1016/S1474-4422(22)00006-0. Correction in: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00038-2.

17. Genentech announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with SMA. https://www.curesma.org/genentech-risdiplam-data-conference-2020/

18. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. doi: 10.1186/s13023-020-1339-3.




 

In 2016, the U.S. Food and Drug Administration approved nusinersen, the first treatment for spinal muscular atrophy (SMA). Until then, SMA had a mortality rate nearly double that of the general population.¹ Two-thirds of patients were symptomatic within 6 months of birth and, in the absence of mechanical ventilation and other support, had a nearly 100% mortality rate by age 2.²

Five years later, there are three approved treatments for SMA, all of which have been shown to slow or even halt disease progression in many patients. These new therapies, coupled with expanded newborn screening and advancements in optimizing patient care, are changing the natural history of the disease and offering a prognosis that extends well beyond adolescence. Neurologists, whose SMA patient population once consisted almost entirely of children, are now treating more adults with the disease. Indeed, more than half of all people alive with SMA in the United States today are adults, according to Cure SMA.

“Managing SMA used to be clinic follow-ups where we were doing our best supportive care and watching people fall apart before our eyes,” said John Brandsema, MD, a physician and neuromuscular section head at the Children’s Hospital of Philadelphia. “Today, what we see in the vast majority of people is that they are either the same as they were before – which is completely against the natural history of this disease and something to be celebrated – or that people are really better with their function. It totally changes everything in the clinic.”

Among those changes are a more proactive approach to rehabilitation and an even greater emphasis on personalized medicine and multidisciplinary care. But there is also a need for updated treatment guidelines, a new classification system to measure disease severity, specific biomarkers to guide therapy choices, more data on long-term efficacy of existing therapeutics, new medications to complement those therapies, and a deeper understanding of a disease that may have treatment options but still has no cure.
 

Advances in early diagnosis

Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which provides instructions for producing a protein called SMN that is critical for the maintenance and function of motor neurons. Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe. SMA is rare, affecting about 1 in 10,000 newborns.

In approximately 96% of patients, SMA is caused by homozygous loss of the SMN1 gene. People with SMA have at least one copy of the SMN2 gene, sometimes called a “backup” gene, that also produces SMN protein. However, a single nucleotide difference between SMN2 and SMN1 causes about 90% of the protein produced by SMN2 to be truncated and less stable. Even with multiple copies of SMN2 present, as is the case with many infants with SMA, the amount of functional protein produced isn’t enough to compensate for the loss of SMN1.³

All three approved medications are SMN up-regulators and work to increase the amount of functional SMN protein. Starting these medications early, even before symptoms present, is critical to preserve motor function. Early treatment depends on early diagnosis, which became more widespread after 2018 when SMA was added to the federally Recommended Uniform Screening Panel for newborns. As of July 1, 2022, 47 states have incorporated SMA newborn screening into their state panel, ensuring that 97% of all infants born in the United States undergo SMA screening shortly after birth. Screening in the remaining states – Hawaii, Nevada, and South Carolina – and Washington, D.C. is expected by mid-2023.

SMA newborn screening is a PCR-based assay that detects homozygous SMN1 gene deletion found in about 95% of all people with SMA. The remaining 5% of cases are caused by various genetic mutations that can only be detected with gene sequencing. In these cases, and in children who don’t undergo SMA newborn screening, the disease is usually identified when symptoms are noticed by a parent, pediatrician, or primary care provider. But a study found that in 2018 only 52.7% of pediatricians correctly identified genetic testing as a requirement for a definitive diagnosis of SMA; in 2019, with a larger sample size, that number decreased to 45%.⁴ The lack of awareness of diagnostic requirements for SMA could contribute to delays in diagnosis, said Mary Schroth, MD, chief medical officer for Cure SMA and a coauthor of the study.

“In our world, suspicion of SMA in an infant is an emergency situation,” Dr. Schroth said. “These babies need to be referred immediately and have genetic testing so that treatment can begin as soon as possible.”

Based on the study findings, Dr. Schroth and others with Cure SMA launched a new tool in 2021 designed to help pediatricians, primary care physicians, and parents identify early signs of SMA, so that a referral to a pediatric neurologist happens quickly. Called SMArt Moves, the educational resource features videos and a checklist to help increase early detection in infants who had a negative SMA newborn screening result or did not receive SMA screening at birth.⁵
 

Who to treat, when, and with which treatment

For many patients, having multiple effective treatment options means that SMA is no longer a fatal disease in early childhood, but one that can be managed into adolescence and adulthood. The question for clinicians is, who do they treat, when, and with which treatment?

Studies have long shown that the number of copies of the backup gene that a patient has is inversely associated with disease severity.⁶ In 2018, a group of SMA experts published a treatment algorithm to help guide decision-making following a positive SMA newborn screening.⁷ The treatment guidelines were updated in 2020 based on clinical trial data for presymptomatic infants, and current recommendations include immediate treatment for infants with two to four copies of the SMN2 gene.⁸ For patients with only one copy of SMN2, most of whom will likely be symptomatic at birth, the guidelines recommend that treatment decisions be made jointly between the clinician and the family.^7,8

Some suggest that the number of SMN2 copies a patient has should also be a factor in determining phenotype, which has started a conversation on the development of a new classification system.⁹ The original classification system for disease severity – Types 0-4 – was based on age of onset and degree of motor function achieved, with Type 0 developing prenatally and being the most severe and Type 4 developing in adulthood. Type 1 is the most common, affecting more than half of all people with SMA, followed by Types 2-4. In 2018, updated consensus care guidelines offered a revised classification system that better reflected disease progression in the age of therapy. The functional motor outcomes include nonsitters (historically Type I), sitters (historically Type 2/3), and walkers (historically Type 3/4).^10,11 These guidelines are a start, but clinicians say more revision is needed.

“Types 1, 2, 3, 4 were based on function – getting to a certain point and then losing it, but now that we can treat this disease, people will shift categories based on therapeutic response or based on normal development that is possible now that the neurologic piece has been stabilized,” Dr. Brandsema said. “We need to completely change our thinking around all these different aspects of SMA management.”

While discussions of a new classification system for SMA are underway, another effort to update treatment recommendations is closer to completion. Led by Cure SMA, a group of about 50 physician experts in the United States and Europe who specialize in SMA are revising guidelines for diagnosis and treatment, the first time the recommendations have been updated since 2018. The updated recommendations, which should be published later this year, will focus on diagnosis and treatment considerations.

“We have three treatments that are available, and there are specific FDA indications for each of those, but it’s not totally clear just how those medications should be used or applied to different clinical situations,” said Dr. Schroth. “We’re in a rapid phase of learning right now in the SMA community, trying to understand how these treatments alter physiology and disease outcomes and how to best use the tools that we now have available to us. In parallel with clinical treatments, we have to be doing the best care we can to optimize the outcomes for those treatments.”
 

Research advances in 2021

Although all three drugs approved to treat SMA – nusinersen (Spinraza; Biogen), onasemnogene abeparvovec-xioi gene replacement therapy (Zolgensma; Novartis Gene Therapies), and risdiplam (Evrysdi, Genentech/Roche) – are highly effective, there are still unanswered questions and unmet needs. New research findings from 2021 focused on higher dosing, different drug-delivery methods, combination therapy, and complementary therapeutics to address SMA comorbidities.

Higher-dose nusinersen. The first drug approved to treat SMA, nusinersen is an antisense oligonucleotide approved for all ages and all SMA types. It works by altering splicing of the SMN2 gene pre-mRNA to make more complete SMN protein. Given as an intrathecal (IT) injection, four “loading doses” are administered within the first 2 months of treatment, followed by a maintenance dose every 4 months for the duration of the individual’s life.

Reports from patients of waning effects of nusinersen just prior to follow-up treatment have led some clinicians to ask if a higher dose may be needed. A study underway seeks to address that issue.

DEVOTE is a phase 2/3 trial to study the safety and efficacy of high-dose nusinersen in patients with SMA. Preliminary findings reported in 2021 found no adverse events among patients treated with 28 mg of nusinersen for 161-257 days.¹² Another analysis from this trial found that higher doses are associated with greater decrease of plasma phosphorylated neurofilament heavy chain (pNF-H) levels in patients with SMA and may lead to clinically meaningful improvement in motor function beyond that observed with the approved 12 mg dose.¹³ The trial is ongoing.

Another trial, ASCEND, is a phase 3B study assessing higher dose nusinersen in patients previously treated with risdiplam. Recruitment for that trial began in October 2021.

Long-term efficacy and IT administration of SMA therapy. Several studies are looking at the long-term efficacy and alternate routes of administration of onasemnogene abeparvovec and other SMA therapies.

A one-time gene replacement therapy delivered via an IV infusion replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene. FDA approved in 2019, it is authorized for use in patients with SMA up to 2 years of age.

The latest data from an ongoing, long-term follow-up safety study of onasemnogene abeparvovec, published in May 2021, suggest that the treatment’s effects persist more than 5 years after treatment. Researchers followed 13 infants with symptomatic SMA type 1 since the beginning of the phase 1 clinical trial of the gene transfer therapy. All patients who received the therapeutic dose maintained their baseline motor function, and two of the patients actually improved without other SMN-targeted treatment. At a median 6.2 years after they received treatment, all were alive and none needed permanent ventilation.¹⁴

After a 2-year hold by the FDA, a study of IT administration of onasemnogene abeparvovec is now enrolling patients. Citing concerns from animal studies that IT administration might result in dorsal root ganglia injury, the FDA issued a partial hold on the STRONG trial in 2019. Following positive study results in nonhuman primates, the FDA announced the trial can continue. Novartis is launching a new phase 3 STEER trial to test the drug delivered intrathecally in patients aged 2-18 years with Type 2 SMA. IT administration could allow the gene therapy to be used safely and effectively in more patients with SMA.

Efficacy of risdiplam in more patients. The first oral treatment for SMA was approved by the FDA in 2020. It’s given once per day in patients with SMA of all ages and disease types. The drug increases functional SMN protein production by the SMN2 gene.

A July 2021 publication of the results of the FIREFISH study found that infants with Type I SMA treated with risdiplam for 12 months were significantly more likely to achieve motor milestones, such as sitting without support, compared with untreated infants with Type 1 SMA.¹⁵ Risdiplam is also effective in older patients with Type 2 or 3 SMA, according to results published in December from the SUNFISH clinical trial.¹⁶ Another study, RAINBOWFISH, is studying safety and efficacy at 24 months in presymptomatic infants started on treatment at up to 6 weeks of age.

The efficacy of risdiplam in previously treated patients is the subject of JEWELFISH, an ongoing study in patients 6 months to 60 years with SMA. Preliminary data presented at the 2020 Virtual SMA Research and Clinical Care Meeting suggest treatment with risdiplam led to a median two-fold increase in the amount of blood SMN protein levels after 4 weeks, which was sustained for at least 24 months.¹⁷

Combination therapy. Among the more eagerly awaited results are those from studies of combination therapies, including those that combine approved SMN up-regulators with new non–SMN-targeted therapeutics.

“We’re seeing that while these three approved therapies have dramatic results, especially for infants who are treated presymptomatically, there are still unmet medical needs in those patients, particularly for older teens and adults whose disease may have progressed before they were able to start therapy,” said Jackie Glascock, PhD, vice president of research for Cure SMA.

Of particular interest are studies of myostatin inhibitors, therapeutics that block the production of the protein myostatin. Myostatin acts on muscle cells to reduce muscle growth. Animal studies suggest that inhibiting myostatin increases muscle mass, which could be important in patients with muscle loss due to SMA.

Three experimental myostatin inhibitors are currently in clinical trials. MANATEE is a global phase 2-3 trial that aims to evaluate the safety and efficacy of the antimyostatin antibody GYM329 (RO7204239) in combination with risdiplam. SAPPHIRE is a phase 3 trial of apitegromab (SRK-015) in combination with nusinersen or risdiplam. RESILIANT is a phase 3 trial of tadefgrobep alfa in combination with other treatments.

A trial is underway to study the efficacy and safety of nusinersen in patients with persistent symptoms of SMA after treatment with the gene therapy. The phase 4 study, RESPOND, is enrolling children aged 2-36 months.

What’s needed next

Despite the advances in treatment and patient care, Dr. Brandsema, Dr. Schroth, and Dr. Glascock note that there remain unmet needs in the SMA community in a variety of areas.

Increased focus on adults with SMA. Before nusinersen, treatment of SMA mainly involved treating its symptoms. Many patients stopped seeing their neurologist, relying more heavily on pulmonary care specialists and/or primary care providers to address breathing, nutrition, and mobility problems. “Now with the approval of these treatments, they’re coming back to see their neurologists and are becoming more visible in the SMA community,” Dr. Schroth said.

Despite this re-emergence, a 2020 meta-analysis of studies on adults with SMA found a paucity of data on physical and occupational therapy, respiratory management, mental health care, and palliative care.¹⁸

“There is just so much work we need to do in the area of adult clinical care of SMA.”

Treatment algorithms. While the development of the newborn screening algorithm and revised patient care guidelines are helpful resources, clinicians still face uncertainty when choosing which therapy will work best for their patients. Treatment algorithms that help clinicians figure out what therapy or combination of therapies will offer the best outcomes for individual patients are desperately needed, Dr. Brandsema said.

“Each person’s experience of this disease is so unique to the individual based partly on their genetics and partly on the factors about what got them into care and how compliant they are with everything we’re trying to do to help them,” he said. “Biomarkers would help clinicians create personalized treatment plans for each patient.”

More basic science. While scientists have a good understanding of the SMN gene, there are many unanswered questions about the function of the SMN protein and its relationship to motor neuron loss. SMN is a ubiquitously expressed protein, and its function in other cell types is largely unknown. Despite all of the research advances, there is much basic science left to be done.

“We are strongly advocating to regulatory authorities that these aren’t cures and we need to continue to invest in the basic research,” Dr. Glascock said. “These biological questions that pertain to SMN and its function and expression really drive drug development. I really think that understanding those pathways better will lead us to more druggable targets.”
 

Two deaths from liver failure linked to spinal muscular atrophy drug

Two children taking the gene therapy drug onasemnogene abeparvovec (Zolgensma, Novartis) for spinal muscular atrophy (SMA) have died from acute liver failure, according to a statement issued by the drug’s manufacturer.

The patients were 4 months and 28 months of age and lived in Russia and Kazakhstan. They died 5-6 weeks after infusion with Zolgensma and approximately 1-10 days after the initiation of a corticosteroid taper.

These are the first known fatal cases of acute liver failure associated with the drug, which the company notes was a known side effect included in the product label and in a boxed warning in the United States.

“Following two recent patient fatalities, and in alignment with health authorities, we will be updating the labeling to specify that fatal acute liver failure has been reported,” the statement reads.

“While this is important safety information, it is not a new safety signal,” it adds.
 

Rare genetic disorder

SMA is a rare genetic disorder that affects about 1 in 10,000 newborns. Patients with SMA lack a working copy of the survival motor neuron 1 (SMN1) gene, which encodes a protein called SMN that is critical for the maintenance and function of motor neurons.

Without this protein, motor neurons eventually die, causing debilitating and progressive muscle weakness that affects the ability to walk, eat, and breathe.

Zolgensma, a one-time gene replacement therapy delivered via intravenous infusion, replaces the function of the missing or nonworking SMN1 gene with a new, working copy of the SMN1 gene.

The first gene therapy treatment for SMA, it was approved by the U.S. Food and Drug Administration in 2019 for patients with SMA up to 2 years of age. It is also the most expensive drug in the world, costing about $2.1 million for a one-time treatment.

“We have notified health authorities in all markets where Zolgensma is used, including the FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” the manufacturer’s statement says.

Studies have suggested that the treatment’s effects persist more than 5 years after infusion.

Clinical trials currently underway by Novartis are studying the drug’s long-term efficacy and safety and its potential use in older patients.

The company is also leading the phase 3 clinical trial STEER to test intrathecal (IT) administration of the drug in patients ages 2-18 years who have type 2 SMA.

That trial began late last year after the FDA lifted a 2-year partial hold on an earlier study. The FDA halted the STRONG trial in 2019, citing concerns from animal studies that IT administration may result in dorsal root ganglia injury. The partial hold was released last fall following positive study results in nonhuman primates.

None of the current trials will be affected by the two deaths reported, according to a Novartis spokesperson.
 

Kelli Whitlock Burton is a staff writer/reporter for Medscape Neurology and MDedge Neurology.

References

1. Viscidi E et al. Comparative all-cause mortality among a large population of patients with spinal muscular atrophy versus matched controls. Neurol Ther. 2022 Mar;11(1):449-457. doi: 10.1007/s40120-021-00307-7.

2. Finkel RS et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-817. doi: 10.1212/WNL.0000000000000741.

3. Klotz J et al. Advances in the therapy of spinal muscular atrophy. J Pediatr. 2021 Sep;236:13-20.e1. doi: 10.1016/j.jpeds.2021.06.033.

4. Curry M et al. Awareness screening and referral patterns among pediatricians in the United States related to early clinical features of spinal muscular atrophy (SMA). BMC Pediatr. 2021 May;21(1):236. doi: 10.1186/s12887-021-02692-2.

5. SMArt Moves. https://smartmoves.curesma.org/

6. Swoboda KJ et al. Natural history of denervation in SMA: Relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.

7. Glascock J et al. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5(2):145-158. doi: 10.3233/JND-180304.

8. Glascock J et al. Revised recommendations for the treatment of infants diagnosed with spinal muscular atrophy via newborn screening who have 4 copies of SMN2. J Neuromuscul Dis. 2020;7(2):97-100. doi: 10.3233/JND-190468.

9. Talbot K, Tizzano EF. The clinical landscape for SMA in a new therapeutic era. Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52.

10. Mercuri E et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-115. doi: 10.1016/j.nmd.2017.11.005.

11. Finkel RS et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207. doi: 10.1016/j.nmd.2017.11.004.

12. Pascual SI et al. Ongoing phase 2/3 DEVOTE (232SM203) randomized, controlled study to explore high-dose nusinersen in SMA: Part A interim results and Part B enrollment update. Presented at MDA Clinical and Scientific Conference 2021, Mar 15-18.

13. Finkel RS et al. Scientific rationale for a higher dose of nusinersen. Presented at 2021 Cure SMA Annual Meeting, Jun 9-11. Abstract P46.

14. Mendell JR et al. Five-year extension results of the phase 1 START trial of onasemnogene abeparvovec in spinal muscular atrophy. JAMA Neurol. 2021 Jul;78(7):834-841. doi: 10.1001/jamaneurol.2021.1272.

15. Darras BT et al. Risdiplam-treated infants with type 1 spinal muscular atrophy versus historical controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.

16. Mercuri E et al. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): A phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2022 Jan;21(1):42-52. doi: 10.1016/S1474-4422(21)00367-7. Erratum in: Lancet Neurol. 2022 Feb;21(2):e2. doi: 10.1016/S1474-4422(22)00006-0. Correction in: Lancet Neurol. 2022 Mar;21(3):e3. doi: 10.1016/S1474-4422(22)00038-2.

17. Genentech announces 2-year risdiplam data from SUNFISH and new data from JEWELFISH in infants, children and adults with SMA. https://www.curesma.org/genentech-risdiplam-data-conference-2020/

18. Wan HWY et al. Health, wellbeing and lived experiences of adults with SMA: a scoping systematic review. Orphanet J Rare Dis. 2020;15(1):70. doi: 10.1186/s13023-020-1339-3.




 

INTRODUCTION

Editor’s note
By Glenn S. Williams
Our 7th annual issue highlights several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing.

A note from NORD
By Peter L. Saltonstall
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.

CLINICAL REVIEWS

Health care providers should have higher suspicion for rare diseases
By Jeff Craven
Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.

The paradox of Pompe disease
By Jennie Smith
For nearly 2 decades, patients with even the most severe genetic mutations have been surviving on therapy. But clinicians must now contend with previously unknown manifestations of this rare muscular disease.

Rett syndrome: Looking to the future and the promise of gene therapy
By Courtney S. Ambrose and Barbara J. Bailus, PhD
Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and conviction, not just hopeful optimism.

Rare disease patient advocacy groups empowered by data
By Theodore Bosworth
On the IAMRARE platform, patient advocacy organizations are trained to conduct observational research and host natural history.

Myasthenia gravis: Finding strength in treatment options
By Peter van der Eb; Scarlet Toruno, MS; and Jason Laird, DMSc, MHS, MBA, PA-C
Although the treatment of myasthenia gravis might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies.

Spinal muscular atrophy: Patient care in the age of genetically targeted therapy
By Kelli Whitlock Burton
Newly available treatments have changed the natural history of SMA. Newborn screening, updated treatment guidelines, and treatment algorithms have likewise changed what can be clinically done for patients with SMA, but still questions remain.

The broad and challenging – but promising – landscape of peripheral neuropathy
By Yun Seo Lee; Jonathan Kosacki; Kanika Bhandari, PharmD; Amanda Tran, PharmD
This review of peripheral neuropathy summarizes the more common causative entities, diagnostic tools that can potentially be employed to identify the disorder, and treatments that are in use or being tested to prevent, slow, or reverse its effects.

NORD Rare Disease Centers of Excellence: A new network seeks to break down barriers in rare disease care
By Jennie Smith
“The goal was to find places that could help with unanswered questions, whether diagnostic questions or treatment questions. To identify places where a patient could reasonably expect to go and have a deeper dive – maybe an interdisciplinary deep dive.”

Staying alert for patients with narcolepsy
By Erik Greb
The chronic neurologic disorder entails not only excessive sleepiness but also social and professional challenges.

ONLINE-ONLY CONTENT

Novel gene-based therapies for neuromuscular diseases
By Nahomi Yewhalashet, MBS, and Larry J. Davis, PharmD
Novel gene-based therapies show significant potential for transforming the treatment of neuromuscular diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, and Duchenne muscular dystrophy.

The urgent need to diagnose Sanfilippo syndrome at an early age
By Theodore Bosworth
The quest for effective treatments is dependent on enrolling more children at a very young age, before loss of milestones.

INTRODUCTION

Editor’s note
By Glenn S. Williams
Our 7th annual issue highlights several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing.

A note from NORD
By Peter L. Saltonstall
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.

CLINICAL REVIEWS

Health care providers should have higher suspicion for rare diseases
By Jeff Craven
Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.

The paradox of Pompe disease
By Jennie Smith
For nearly 2 decades, patients with even the most severe genetic mutations have been surviving on therapy. But clinicians must now contend with previously unknown manifestations of this rare muscular disease.

Rett syndrome: Looking to the future and the promise of gene therapy
By Courtney S. Ambrose and Barbara J. Bailus, PhD
Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and conviction, not just hopeful optimism.

Rare disease patient advocacy groups empowered by data
By Theodore Bosworth
On the IAMRARE platform, patient advocacy organizations are trained to conduct observational research and host natural history.

Myasthenia gravis: Finding strength in treatment options
By Peter van der Eb; Scarlet Toruno, MS; and Jason Laird, DMSc, MHS, MBA, PA-C
Although the treatment of myasthenia gravis might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies.

Spinal muscular atrophy: Patient care in the age of genetically targeted therapy
By Kelli Whitlock Burton
Newly available treatments have changed the natural history of SMA. Newborn screening, updated treatment guidelines, and treatment algorithms have likewise changed what can be clinically done for patients with SMA, but still questions remain.

The broad and challenging – but promising – landscape of peripheral neuropathy
By Yun Seo Lee; Jonathan Kosacki; Kanika Bhandari, PharmD; Amanda Tran, PharmD
This review of peripheral neuropathy summarizes the more common causative entities, diagnostic tools that can potentially be employed to identify the disorder, and treatments that are in use or being tested to prevent, slow, or reverse its effects.

NORD Rare Disease Centers of Excellence: A new network seeks to break down barriers in rare disease care
By Jennie Smith
“The goal was to find places that could help with unanswered questions, whether diagnostic questions or treatment questions. To identify places where a patient could reasonably expect to go and have a deeper dive – maybe an interdisciplinary deep dive.”

Staying alert for patients with narcolepsy
By Erik Greb
The chronic neurologic disorder entails not only excessive sleepiness but also social and professional challenges.

ONLINE-ONLY CONTENT

Novel gene-based therapies for neuromuscular diseases
By Nahomi Yewhalashet, MBS, and Larry J. Davis, PharmD
Novel gene-based therapies show significant potential for transforming the treatment of neuromuscular diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, and Duchenne muscular dystrophy.

The urgent need to diagnose Sanfilippo syndrome at an early age
By Theodore Bosworth
The quest for effective treatments is dependent on enrolling more children at a very young age, before loss of milestones.

INTRODUCTION

Editor’s note
By Glenn S. Williams
Our 7th annual issue highlights several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing.

A note from NORD
By Peter L. Saltonstall
As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.

CLINICAL REVIEWS

Health care providers should have higher suspicion for rare diseases
By Jeff Craven
Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.

The paradox of Pompe disease
By Jennie Smith
For nearly 2 decades, patients with even the most severe genetic mutations have been surviving on therapy. But clinicians must now contend with previously unknown manifestations of this rare muscular disease.

Rett syndrome: Looking to the future and the promise of gene therapy
By Courtney S. Ambrose and Barbara J. Bailus, PhD
Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and conviction, not just hopeful optimism.

Rare disease patient advocacy groups empowered by data
By Theodore Bosworth
On the IAMRARE platform, patient advocacy organizations are trained to conduct observational research and host natural history.

Myasthenia gravis: Finding strength in treatment options
By Peter van der Eb; Scarlet Toruno, MS; and Jason Laird, DMSc, MHS, MBA, PA-C
Although the treatment of myasthenia gravis might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies.

Spinal muscular atrophy: Patient care in the age of genetically targeted therapy
By Kelli Whitlock Burton
Newly available treatments have changed the natural history of SMA. Newborn screening, updated treatment guidelines, and treatment algorithms have likewise changed what can be clinically done for patients with SMA, but still questions remain.

The broad and challenging – but promising – landscape of peripheral neuropathy
By Yun Seo Lee; Jonathan Kosacki; Kanika Bhandari, PharmD; Amanda Tran, PharmD
This review of peripheral neuropathy summarizes the more common causative entities, diagnostic tools that can potentially be employed to identify the disorder, and treatments that are in use or being tested to prevent, slow, or reverse its effects.

NORD Rare Disease Centers of Excellence: A new network seeks to break down barriers in rare disease care
By Jennie Smith
“The goal was to find places that could help with unanswered questions, whether diagnostic questions or treatment questions. To identify places where a patient could reasonably expect to go and have a deeper dive – maybe an interdisciplinary deep dive.”

Staying alert for patients with narcolepsy
By Erik Greb
The chronic neurologic disorder entails not only excessive sleepiness but also social and professional challenges.

ONLINE-ONLY CONTENT

Novel gene-based therapies for neuromuscular diseases
By Nahomi Yewhalashet, MBS, and Larry J. Davis, PharmD
Novel gene-based therapies show significant potential for transforming the treatment of neuromuscular diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy, and Duchenne muscular dystrophy.

The urgent need to diagnose Sanfilippo syndrome at an early age
By Theodore Bosworth
The quest for effective treatments is dependent on enrolling more children at a very young age, before loss of milestones.

With the goal of advancing treatment of rare neurological diseases – or rare diseases of any type – the National Organization for Rare Disorders (NORD) has launched innovative new research initiatives in recent years to help patient advocacy organizations develop a precious asset: data to support better understanding of diseases and research that might lead to life-altering diagnostics or treatments.

Data empowers research

While NORD helps groups through the IAMRARE program to become research-ready and guides them in developing research protocols and goals, the data are ultimately owned by the patient advocacy groups themselves. This helps to ensure that the patient voice is heard. By controlling data collection and dissemination, the advocacy groups can take a leading role in defining the goals of research, including what outcome measures are important to them and what they agree are the most promising avenues for research to achieve those goals.

“By collecting the data to understand the disease, it sets the stage for the next steps in research,” explained Debbie Drell, the director of membership for NORD. She noted that IAMRARE has grown steadily since its inception in 2014 and that there are now close to 40 advocacy groups participating.

The value of this initiative is not difficult to grasp. Even though direct participation in research was not generally part of the agenda for some advocacy groups when IAMRARE was conceived, Ms. Drell said that this initiative is a compelling perk of becoming involved with NORD. Groups that elect to become research-ready in order to participate in IAMRARE fall into a category of membership that requires specific organizational structures – such as a medical advisory board – and NORD provides templates and guidance to help them meet these qualifications to successfully become research-ready.
 

Collaboration leads to progress

NORD was founded by an ad hoc committee of patient organizations that played a key role in enactment of the Orphan Drug Act nearly 40 years ago. Shortly after the Orphan Drug Act was passed by Congress and signed into law by President Ronald Reagan in 1983, the ad hoc committee formally united to create NORD to continue the momentum of this initial collaboration and support the rare disease community. According to Mary Dunkle, a senior advisor at NORD, passage of the Orphan Drug Act, which is widely considered a major driver of progress in development of treatments for rare diseases, made the advantages of their cooperation clear.

“The groups had so many issues in common across the spectrum of diseases that they decided to continue their collaboration,” she explained. ”They realized that, while each disease is rare, the challenges they present to patients, families, clinicians, and researchers have many similarities.”

The definition of rare disease, according to the National Institutes of Health, is a disorder that affects fewer than 200,000 people in the United States. More than 7,000 such disorders have been identified. Approximately one-third of rare diseases are neurological. Whether neurological or affecting different or multiple organ systems, most – perhaps 75%-80% – involve a genetic component, according to Ms. Dunkle.
 

Research reaps rewards

Altogether, today there are more than 1,000 patient organizations that provide various types of support and services for patients and caregivers affected by rare diseases. Approximately one-third of these organizations are members of NORD. For organizations that don’t yet meet the membership criteria or for other reasons have not yet formally joined NORD, there are still many opportunities to get involved and to learn best practices to strengthen their governance, infrastructure, and capacity to support their members.

Of these, the IAMRARE program is one of the best examples of ways to get involved. Beyond the many other ways these groups help patients and families cope with challenging diseases, participation in research takes rare disorder advocacy to a different level. Objective data can attract the attention of those with the resources to further study the disease, while also giving advocacy groups a seat at the table when researchers or industry become interested.

“Why create a registry? It removes competition between academic centers or industry working on their own. It creates one central source for data-sharing, and the advantage is that advocacy groups have a trusted relationship with the patient community because they are not-for-profit, community-run, and patient-driven,” Ms. Drell explained.

The registry platforms developed for IAMRARE are customizable. With guidance from NORD, the advocacy groups themselves decide what data to collect and what questions they wish to answer, according to Dr. Fink. Once the registries are created, patients and caregivers participate by responding to survey questions on disease onset, progression over time, types and severity of symptoms, and other topics. The data can be de-identified for research purposes. The advocacy groups decide how and when to share the data, including whether to publish findings.

“Some of the groups have been very successful in getting the data published and leveraging their results to drive research forward, but there is variability in the extent of dissemination across the groups,” said Dr. Fink. She noted that many of the registries that NORD has helped set up involve groups whose officers have had little or no prior research experience.

“We have advocacy groups that have had biomedical researchers on staff and other groups that are coming to research completely new,” Dr. Fink said. In trying to get them up to speed on quality data collection, “We try to meet them where they are,” she added, indicating that leading groups to a research-ready status is not just about logistics but can sometimes involve an organizational reorientation.

The examples of peer-reviewed publications that can be directly traced to IAMRARE registries are growing. One example is a registry on Prader-Willi syndrome, which is a complex neurodevelopmental disorder characterized by failure to thrive and by multiple endocrine abnormalities. The registry was developed in NORD’s IAMRARE program by the Foundation for Prader-Willi Research, a nonprofit created in 2003 by parents of children with this disorder.

By 2019, when the first data from the Global Prader-Willi Syndrome Registry were published, they drew from 23,550 surveys completed for 1,696 separate cases of the disorder in 37 countries. The surveys provided some preliminary findings on demographics and on the genetic subtypes most commonly encountered, as well as simply proof that the registry was viable. From its inception in 2015, a significant proportion of the Prader-Willi population in the United States had been enrolled, according to the study authors. With time, the serial accumulation of more data on more cases will be invaluable for documenting disease characteristics. It will be a constantly maturing resource even after fundamental questions on disease impact and prognosis are addressed.
 

Data accumulation

Only about 10% of rare diseases currently have approved treatments, but there is widespread belief in the rare community that collecting and analyzing the data that can promote understanding of the biology of the disease and identify therapeutic targets could accelerate the development of treatments for diseases that currently have none.

Therefore, data accumulation has become central to the mission of NORD. In addition to IAMRARE, the organization has embarked on several other important initiatives in data accumulation for rare diseases. One is the Rare Disease Cures Accelerator – Data and Analytics Platform (RDCA-DAP), an initiative in which NORD is partnering with the Critical Path Institute. The goal of this program is to gather disparate pools of existing data in a standardized format to increase their power.

“With funding from the Food and Drug Administration, we have helped to support this platform, which is designed specifically to provide a centralized structure for combining and sharing of data,” according to Dr. Fink. In RDCA-DAP, patient-level data is being assembled from a variety of resources, including academic centers, industry, registries, observational studies, and clinical trials. The program was launched in September 2021. In some cases, gaining access to data includes resolving privacy issues or addressing the proprietary concerns of those who currently have the data, but the value of the combined data is a compelling argument for participation.

“What we are trying to do is pull together the data from their current silos into one platform, and then make it generally available,” said Dr. Fink. As with IAMRARE, RDCA-DAP offers enormous potential.

“The primary challenge for those studying rare diseases is the small numbers of patients. Randomized clinical trials for some of these diseases are simply not feasible because there are not enough subjects to power two study arms,” said Dr. Fink in explaining why NORD has turned to novel strategies for data generation. One strategy for maximizing the potential value of data from these small populations of patients is data-sharing. For RDCA-DAP, data access will be open to all stakeholders after scientific review and approval.

“Anyone can get an account and request data from the platform,” said Dr. Fink, who expects this to spur more and novel types of research in rare disorders.

Another example of recent NORD initiatives to advance research and understanding of rare diseases is a study of metachromatic leukodystrophy (MLD) that is now enrolling patients, which also represents a partnership with the FDA. For this study, which is known as the HOME study, NORD hosts a platform where patients and caregivers enter data to capture the natural history of this disease. All MLD patients, even if they are already participating in a clinical trial or another registry, are invited. As with the IAMRARE registries, surveys capture patient or caregiver responses entered from a computer or smart device.

“We have always believed that the fact that so many rare diseases don’t have treatments or are not even being studied by researchers doesn’t reflect a lack of interest among academic or industry researchers. Rather, it reflects a lack of data to support research and to provide a fundamental understanding of the disease,” Dr. Fink said. “If NORD’s expanded research programs can draw the patient community together to provide that crucially needed data, we will have provided an important and essential service to patients, patient organizations, and researchers alike.”

Theodore Bosworth is a freelance journalist and editor specializing in medicine and health.

With the goal of advancing treatment of rare neurological diseases – or rare diseases of any type – the National Organization for Rare Disorders (NORD) has launched innovative new research initiatives in recent years to help patient advocacy organizations develop a precious asset: data to support better understanding of diseases and research that might lead to life-altering diagnostics or treatments.

Data empowers research

While NORD helps groups through the IAMRARE program to become research-ready and guides them in developing research protocols and goals, the data are ultimately owned by the patient advocacy groups themselves. This helps to ensure that the patient voice is heard. By controlling data collection and dissemination, the advocacy groups can take a leading role in defining the goals of research, including what outcome measures are important to them and what they agree are the most promising avenues for research to achieve those goals.

“By collecting the data to understand the disease, it sets the stage for the next steps in research,” explained Debbie Drell, the director of membership for NORD. She noted that IAMRARE has grown steadily since its inception in 2014 and that there are now close to 40 advocacy groups participating.

The value of this initiative is not difficult to grasp. Even though direct participation in research was not generally part of the agenda for some advocacy groups when IAMRARE was conceived, Ms. Drell said that this initiative is a compelling perk of becoming involved with NORD. Groups that elect to become research-ready in order to participate in IAMRARE fall into a category of membership that requires specific organizational structures – such as a medical advisory board – and NORD provides templates and guidance to help them meet these qualifications to successfully become research-ready.
 

Collaboration leads to progress

NORD was founded by an ad hoc committee of patient organizations that played a key role in enactment of the Orphan Drug Act nearly 40 years ago. Shortly after the Orphan Drug Act was passed by Congress and signed into law by President Ronald Reagan in 1983, the ad hoc committee formally united to create NORD to continue the momentum of this initial collaboration and support the rare disease community. According to Mary Dunkle, a senior advisor at NORD, passage of the Orphan Drug Act, which is widely considered a major driver of progress in development of treatments for rare diseases, made the advantages of their cooperation clear.

“The groups had so many issues in common across the spectrum of diseases that they decided to continue their collaboration,” she explained. ”They realized that, while each disease is rare, the challenges they present to patients, families, clinicians, and researchers have many similarities.”

The definition of rare disease, according to the National Institutes of Health, is a disorder that affects fewer than 200,000 people in the United States. More than 7,000 such disorders have been identified. Approximately one-third of rare diseases are neurological. Whether neurological or affecting different or multiple organ systems, most – perhaps 75%-80% – involve a genetic component, according to Ms. Dunkle.
 

Research reaps rewards

Altogether, today there are more than 1,000 patient organizations that provide various types of support and services for patients and caregivers affected by rare diseases. Approximately one-third of these organizations are members of NORD. For organizations that don’t yet meet the membership criteria or for other reasons have not yet formally joined NORD, there are still many opportunities to get involved and to learn best practices to strengthen their governance, infrastructure, and capacity to support their members.

Of these, the IAMRARE program is one of the best examples of ways to get involved. Beyond the many other ways these groups help patients and families cope with challenging diseases, participation in research takes rare disorder advocacy to a different level. Objective data can attract the attention of those with the resources to further study the disease, while also giving advocacy groups a seat at the table when researchers or industry become interested.

“Why create a registry? It removes competition between academic centers or industry working on their own. It creates one central source for data-sharing, and the advantage is that advocacy groups have a trusted relationship with the patient community because they are not-for-profit, community-run, and patient-driven,” Ms. Drell explained.

The registry platforms developed for IAMRARE are customizable. With guidance from NORD, the advocacy groups themselves decide what data to collect and what questions they wish to answer, according to Dr. Fink. Once the registries are created, patients and caregivers participate by responding to survey questions on disease onset, progression over time, types and severity of symptoms, and other topics. The data can be de-identified for research purposes. The advocacy groups decide how and when to share the data, including whether to publish findings.

“Some of the groups have been very successful in getting the data published and leveraging their results to drive research forward, but there is variability in the extent of dissemination across the groups,” said Dr. Fink. She noted that many of the registries that NORD has helped set up involve groups whose officers have had little or no prior research experience.

“We have advocacy groups that have had biomedical researchers on staff and other groups that are coming to research completely new,” Dr. Fink said. In trying to get them up to speed on quality data collection, “We try to meet them where they are,” she added, indicating that leading groups to a research-ready status is not just about logistics but can sometimes involve an organizational reorientation.

The examples of peer-reviewed publications that can be directly traced to IAMRARE registries are growing. One example is a registry on Prader-Willi syndrome, which is a complex neurodevelopmental disorder characterized by failure to thrive and by multiple endocrine abnormalities. The registry was developed in NORD’s IAMRARE program by the Foundation for Prader-Willi Research, a nonprofit created in 2003 by parents of children with this disorder.

By 2019, when the first data from the Global Prader-Willi Syndrome Registry were published, they drew from 23,550 surveys completed for 1,696 separate cases of the disorder in 37 countries. The surveys provided some preliminary findings on demographics and on the genetic subtypes most commonly encountered, as well as simply proof that the registry was viable. From its inception in 2015, a significant proportion of the Prader-Willi population in the United States had been enrolled, according to the study authors. With time, the serial accumulation of more data on more cases will be invaluable for documenting disease characteristics. It will be a constantly maturing resource even after fundamental questions on disease impact and prognosis are addressed.
 

Data accumulation

Only about 10% of rare diseases currently have approved treatments, but there is widespread belief in the rare community that collecting and analyzing the data that can promote understanding of the biology of the disease and identify therapeutic targets could accelerate the development of treatments for diseases that currently have none.

Therefore, data accumulation has become central to the mission of NORD. In addition to IAMRARE, the organization has embarked on several other important initiatives in data accumulation for rare diseases. One is the Rare Disease Cures Accelerator – Data and Analytics Platform (RDCA-DAP), an initiative in which NORD is partnering with the Critical Path Institute. The goal of this program is to gather disparate pools of existing data in a standardized format to increase their power.

“With funding from the Food and Drug Administration, we have helped to support this platform, which is designed specifically to provide a centralized structure for combining and sharing of data,” according to Dr. Fink. In RDCA-DAP, patient-level data is being assembled from a variety of resources, including academic centers, industry, registries, observational studies, and clinical trials. The program was launched in September 2021. In some cases, gaining access to data includes resolving privacy issues or addressing the proprietary concerns of those who currently have the data, but the value of the combined data is a compelling argument for participation.

“What we are trying to do is pull together the data from their current silos into one platform, and then make it generally available,” said Dr. Fink. As with IAMRARE, RDCA-DAP offers enormous potential.

“The primary challenge for those studying rare diseases is the small numbers of patients. Randomized clinical trials for some of these diseases are simply not feasible because there are not enough subjects to power two study arms,” said Dr. Fink in explaining why NORD has turned to novel strategies for data generation. One strategy for maximizing the potential value of data from these small populations of patients is data-sharing. For RDCA-DAP, data access will be open to all stakeholders after scientific review and approval.

“Anyone can get an account and request data from the platform,” said Dr. Fink, who expects this to spur more and novel types of research in rare disorders.

Another example of recent NORD initiatives to advance research and understanding of rare diseases is a study of metachromatic leukodystrophy (MLD) that is now enrolling patients, which also represents a partnership with the FDA. For this study, which is known as the HOME study, NORD hosts a platform where patients and caregivers enter data to capture the natural history of this disease. All MLD patients, even if they are already participating in a clinical trial or another registry, are invited. As with the IAMRARE registries, surveys capture patient or caregiver responses entered from a computer or smart device.

“We have always believed that the fact that so many rare diseases don’t have treatments or are not even being studied by researchers doesn’t reflect a lack of interest among academic or industry researchers. Rather, it reflects a lack of data to support research and to provide a fundamental understanding of the disease,” Dr. Fink said. “If NORD’s expanded research programs can draw the patient community together to provide that crucially needed data, we will have provided an important and essential service to patients, patient organizations, and researchers alike.”

Theodore Bosworth is a freelance journalist and editor specializing in medicine and health.

With the goal of advancing treatment of rare neurological diseases – or rare diseases of any type – the National Organization for Rare Disorders (NORD) has launched innovative new research initiatives in recent years to help patient advocacy organizations develop a precious asset: data to support better understanding of diseases and research that might lead to life-altering diagnostics or treatments.

Data empowers research

While NORD helps groups through the IAMRARE program to become research-ready and guides them in developing research protocols and goals, the data are ultimately owned by the patient advocacy groups themselves. This helps to ensure that the patient voice is heard. By controlling data collection and dissemination, the advocacy groups can take a leading role in defining the goals of research, including what outcome measures are important to them and what they agree are the most promising avenues for research to achieve those goals.

“By collecting the data to understand the disease, it sets the stage for the next steps in research,” explained Debbie Drell, the director of membership for NORD. She noted that IAMRARE has grown steadily since its inception in 2014 and that there are now close to 40 advocacy groups participating.

The value of this initiative is not difficult to grasp. Even though direct participation in research was not generally part of the agenda for some advocacy groups when IAMRARE was conceived, Ms. Drell said that this initiative is a compelling perk of becoming involved with NORD. Groups that elect to become research-ready in order to participate in IAMRARE fall into a category of membership that requires specific organizational structures – such as a medical advisory board – and NORD provides templates and guidance to help them meet these qualifications to successfully become research-ready.
 

Collaboration leads to progress

NORD was founded by an ad hoc committee of patient organizations that played a key role in enactment of the Orphan Drug Act nearly 40 years ago. Shortly after the Orphan Drug Act was passed by Congress and signed into law by President Ronald Reagan in 1983, the ad hoc committee formally united to create NORD to continue the momentum of this initial collaboration and support the rare disease community. According to Mary Dunkle, a senior advisor at NORD, passage of the Orphan Drug Act, which is widely considered a major driver of progress in development of treatments for rare diseases, made the advantages of their cooperation clear.

“The groups had so many issues in common across the spectrum of diseases that they decided to continue their collaboration,” she explained. ”They realized that, while each disease is rare, the challenges they present to patients, families, clinicians, and researchers have many similarities.”

The definition of rare disease, according to the National Institutes of Health, is a disorder that affects fewer than 200,000 people in the United States. More than 7,000 such disorders have been identified. Approximately one-third of rare diseases are neurological. Whether neurological or affecting different or multiple organ systems, most – perhaps 75%-80% – involve a genetic component, according to Ms. Dunkle.
 

Research reaps rewards

Altogether, today there are more than 1,000 patient organizations that provide various types of support and services for patients and caregivers affected by rare diseases. Approximately one-third of these organizations are members of NORD. For organizations that don’t yet meet the membership criteria or for other reasons have not yet formally joined NORD, there are still many opportunities to get involved and to learn best practices to strengthen their governance, infrastructure, and capacity to support their members.

Of these, the IAMRARE program is one of the best examples of ways to get involved. Beyond the many other ways these groups help patients and families cope with challenging diseases, participation in research takes rare disorder advocacy to a different level. Objective data can attract the attention of those with the resources to further study the disease, while also giving advocacy groups a seat at the table when researchers or industry become interested.

“Why create a registry? It removes competition between academic centers or industry working on their own. It creates one central source for data-sharing, and the advantage is that advocacy groups have a trusted relationship with the patient community because they are not-for-profit, community-run, and patient-driven,” Ms. Drell explained.

The registry platforms developed for IAMRARE are customizable. With guidance from NORD, the advocacy groups themselves decide what data to collect and what questions they wish to answer, according to Dr. Fink. Once the registries are created, patients and caregivers participate by responding to survey questions on disease onset, progression over time, types and severity of symptoms, and other topics. The data can be de-identified for research purposes. The advocacy groups decide how and when to share the data, including whether to publish findings.

“Some of the groups have been very successful in getting the data published and leveraging their results to drive research forward, but there is variability in the extent of dissemination across the groups,” said Dr. Fink. She noted that many of the registries that NORD has helped set up involve groups whose officers have had little or no prior research experience.

“We have advocacy groups that have had biomedical researchers on staff and other groups that are coming to research completely new,” Dr. Fink said. In trying to get them up to speed on quality data collection, “We try to meet them where they are,” she added, indicating that leading groups to a research-ready status is not just about logistics but can sometimes involve an organizational reorientation.

The examples of peer-reviewed publications that can be directly traced to IAMRARE registries are growing. One example is a registry on Prader-Willi syndrome, which is a complex neurodevelopmental disorder characterized by failure to thrive and by multiple endocrine abnormalities. The registry was developed in NORD’s IAMRARE program by the Foundation for Prader-Willi Research, a nonprofit created in 2003 by parents of children with this disorder.

By 2019, when the first data from the Global Prader-Willi Syndrome Registry were published, they drew from 23,550 surveys completed for 1,696 separate cases of the disorder in 37 countries. The surveys provided some preliminary findings on demographics and on the genetic subtypes most commonly encountered, as well as simply proof that the registry was viable. From its inception in 2015, a significant proportion of the Prader-Willi population in the United States had been enrolled, according to the study authors. With time, the serial accumulation of more data on more cases will be invaluable for documenting disease characteristics. It will be a constantly maturing resource even after fundamental questions on disease impact and prognosis are addressed.
 

Data accumulation

Only about 10% of rare diseases currently have approved treatments, but there is widespread belief in the rare community that collecting and analyzing the data that can promote understanding of the biology of the disease and identify therapeutic targets could accelerate the development of treatments for diseases that currently have none.

Therefore, data accumulation has become central to the mission of NORD. In addition to IAMRARE, the organization has embarked on several other important initiatives in data accumulation for rare diseases. One is the Rare Disease Cures Accelerator – Data and Analytics Platform (RDCA-DAP), an initiative in which NORD is partnering with the Critical Path Institute. The goal of this program is to gather disparate pools of existing data in a standardized format to increase their power.

“With funding from the Food and Drug Administration, we have helped to support this platform, which is designed specifically to provide a centralized structure for combining and sharing of data,” according to Dr. Fink. In RDCA-DAP, patient-level data is being assembled from a variety of resources, including academic centers, industry, registries, observational studies, and clinical trials. The program was launched in September 2021. In some cases, gaining access to data includes resolving privacy issues or addressing the proprietary concerns of those who currently have the data, but the value of the combined data is a compelling argument for participation.

“What we are trying to do is pull together the data from their current silos into one platform, and then make it generally available,” said Dr. Fink. As with IAMRARE, RDCA-DAP offers enormous potential.

“The primary challenge for those studying rare diseases is the small numbers of patients. Randomized clinical trials for some of these diseases are simply not feasible because there are not enough subjects to power two study arms,” said Dr. Fink in explaining why NORD has turned to novel strategies for data generation. One strategy for maximizing the potential value of data from these small populations of patients is data-sharing. For RDCA-DAP, data access will be open to all stakeholders after scientific review and approval.

“Anyone can get an account and request data from the platform,” said Dr. Fink, who expects this to spur more and novel types of research in rare disorders.

Another example of recent NORD initiatives to advance research and understanding of rare diseases is a study of metachromatic leukodystrophy (MLD) that is now enrolling patients, which also represents a partnership with the FDA. For this study, which is known as the HOME study, NORD hosts a platform where patients and caregivers enter data to capture the natural history of this disease. All MLD patients, even if they are already participating in a clinical trial or another registry, are invited. As with the IAMRARE registries, surveys capture patient or caregiver responses entered from a computer or smart device.

“We have always believed that the fact that so many rare diseases don’t have treatments or are not even being studied by researchers doesn’t reflect a lack of interest among academic or industry researchers. Rather, it reflects a lack of data to support research and to provide a fundamental understanding of the disease,” Dr. Fink said. “If NORD’s expanded research programs can draw the patient community together to provide that crucially needed data, we will have provided an important and essential service to patients, patient organizations, and researchers alike.”

Theodore Bosworth is a freelance journalist and editor specializing in medicine and health.

The dream of curing genetic disorders has been a persistent but elusive goal, even before the human genome was mapped. Once mapping of the human genome was complete in 2001, an entirely new avenue of potential treatments and cures for genetic diseases and disorders was opened.^1,2

One of the rare monogenic disorders that is embracing multiple gene therapy approaches is Rett syndrome, a rare, debilitating neurodevelopmental disorder. In this review, we explore the molecular cause of Rett syndrome, disease presentation, current treatments, ongoing clinical trials, and therapies that are on the horizon.
 

Underlying molecular cause

Rett syndrome is caused by mutations in, or the absence of, the MECP2 gene, which produces methyl-CpG binding protein 2 (MECP2). The syndrome was first described clinically in 1954 by the Austrian physician Andreas Rett; it would take until 1982 before the disorder was officially named, eponymously, in a seminal paper by Hagberg.⁴ After Hagberg’s characterization, Rett syndrome became the predominant global clinical diagnosis identified among cognitively impaired females, with an incidence of 1 in every 10,000 to 15,000.⁴

In 1999, mutations in, and deletions of, MECP2 were identified as the cause of Rett syndrome.^4,5 MECP2 is located on the X chromosome, in the Xq28 region, making Rett syndrome an X-linked dominant disorder.⁶ Rett syndrome is seen predominantly in females who are mosaic for mutant or deleted MECP2. Random X chromosome inactivation results in some cells expressing the mutant MECP2 allele and other cells expressing the normal functioning MECP2 allele; the percentage of cells expressing the normal allele correlates with the degree of syndrome severity.^7-9

The incidence of Rett syndrome is much lower in males, in whom the syndrome was originally thought to be lethal; many observed male cases are either mosaic or occur in XXY males.^10,11

Approximately 95% of cases of Rett syndrome are due to de novo mutations in MECP2, with a handful of specific mutations and large deletions accounting for more than 85% of cases.¹² The fact that Rett syndrome is monogenic and most cases are caused by, in total, only a handful of mutations or deletions makes the syndrome a promising candidate for gene therapy.

At the molecular level, it has been observed that the MECP2 mutations of Rett syndrome lead to loss of gene function, thus disrupting the ability of the MECP2 nuclear protein to regulate global gene transcription through its binding to methylated DNA sites.¹² A large percentage of these missense and nonsense mutations lead to a truncated or nonfunctional protein.¹²

One of the ways in which MECP2 regulates transcription is as a component of heterochromatin condensates and by separation of heterochromatin and euchromatin.^13-15 It has been observed that the cells of Rett syndrome patients have an altered chromatin state, potentially contributing to transcriptional dysregulation.^16,17 Several mutations observed in Rett syndrome patients occur in crucial domains for heterochromatin condensate formation, which helps explain this cellular phenotype.¹³ Introduction of a engineered “mini” MECP2 in a murine model of Rett syndrome has resulted in partial rescue of heterochromatin condensate formation and transcriptional regulation – fostering the hypothesis that correcting those genetic changes could lead to a potential therapy.¹⁸

Beyond the role of MECP2 in heterochromatin condensate formation, the gene interacts with more than 40 proteins that have diverse roles in cellular function, epigenetic modulation, and neuronal development. This volume of interactions contributes to MECP2 being a global gene regulatory protein that has far-reaching effects on transcriptional regulation across the genome.^19-22

Epigenetic dysregulation has been associated with neurodevelopmental and neuropsychiatric disorders.²³ Both insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor are transcriptional targets of MECP2, and are involved in neuronal differentiation, synaptic function, and neurite outgrowth.¹² This helps explain the neurodevelopmental phenotypes observed in MECP2-mutated patients.

Notably, although Rett syndrome patients experience neurodevelopmental phenotypes at the cellular level, neuronal death is not readily observed. That observation provides hope that an interventional therapy after onset of symptoms might still be of benefit.
 

Presentation

Early neurotypical development. A hallmark of Rett syndrome is neurotypical physical and mental development until 6 to 24 months of age.

Stagnation is the first stage of the syndrome, involving a small but rapid decline in habitual milestones, such motor and language skills.¹² Subtle signs, such as microcephaly and hypotonia, can also arise at this time but might be missed.²⁴

Rapid regression follows stagnation. Speech and motor delays and impaired gait and breathing occur;^12,25 purposeful hand skills are lost, replaced by repetitive hand-wringing movements that are a hallmark of the syndrome.^12,24 Seizures are observed; they become more common during the next stage.¹²

Plateau. Language advances can be observed, but further deficits are seen in motor skills and hand coordination.¹²

Late motor deterioration stage. Late physical deficits develop, leading to lifelong impairments. The physical deficits observed are the result of severe muscle weakness, usually resulting in wheelchair dependency.¹²

Plateau. Patients then reach a second plateau. Regression stops; deficient physical and cognitive states stabilize and are maintained.²⁵

At all stages of Rett syndrome, the following are observed:

• Gastrointestinal problems.
• Sleep disturbances.
• Abnormal cardiorespiratory coupling.
• Greater-than-expected mortality.¹²

Final regression. The patient is fully dependent for the rest of their lifespan, partially due to seizure activity.^26,27
 

A life-changing diagnosis

A diagnosis of Rett syndrome is life-changing for a patient’s family; access to supportive groups of other patients and their families is extremely beneficial. Two helpful organizations – the Rett Syndrome Research Trust²⁸ and International Rett Syndrome Foundation,²⁹ – offer patient support and community and fund research.

Because X chromosome inactivation is random in Rett syndrome, the individual patient can present with a wide variety of phenotypic combinations – making the patient, and their needs, unique.¹² During stages of regression, patients often experience emotional dysregulation and anxiety, which is attributable to their increasing physical difficulties.³⁰ They often exhibit combinations of uncontrolled movements, including repetitive rocking, scratching, and self-injurious behavior.³⁰ For most, regression subsides after the first 5 years of alternating development and regression; after that, their ultimate symptoms persist for life.²⁵

As patients mature, they need to be monitored for proper nutrition and scoliosis.²⁵ As adults, they are at risk of pneumonia, respiratory distress, status epilepticus, osteopenia, and lack of adequate food or water because of impaired ability to feed.²⁵

The lifespan of Rett syndrome patients has increased, thanks to improvements in health care, advances in technology, and early genetic testing, which allows for earlier diagnosis, intervention, and management of symptoms.
 

Current treatments

When a female patient presents with regression and loss of milestones, sequencing of MECP2 is performed to verify whether Rett syndrome is the cause, by detecting any of the known mutations. Multiplex ligation-dependent probe amplification is also performed to detect major deletions.²⁵

All available treatments for Rett syndrome are symptomatic; intensive early intervention is practiced.³¹ Multidisciplinary management – medical, psychiatric, and physical – is introduced almost immediately after diagnosis. Following diagnosis, patients are prescribed anti-seizure, sleep, and anxiety medications.³¹ Electroencephalography can be performed to identify seizure type. Neuromuscular blockage drugs can be prescribed to help with gait and stereotypic hand movements.²⁵

Handguards or splints to the elbows can be prescribed by an occupational therapist to improve hand movement.²⁵ Physical therapy can improve mobility; hydrotherapy and hippotherapy have been successful in helping to maintain mobility and muscle support.^32,33 Nutritional management is implemented to control caloric intake and maintain the vitamin D level.³¹ Some patients experience constipation and urinary retention, putting them at risk of nephrolithiasis.

Once the signs and symptoms of Rett syndrome progress, and milestones regress to a certain point, patients need constant, full-time care for the rest of their lives.³⁴ As symptomatic interventions have greatly improved patient outcomes and it has been shown that about 70% can reach adulthood with a potential lifespan of about 50 years.²⁵

Although there is no cure for Rett syndrome and treatments are symptomatic, ongoing studies – both clinical and preclinical – offer promise that treatments will be developed that work at molecular and genetic levels.
 

Clinical trials

Advances in understanding of Rett syndrome have led to many therapies in clinical trials, several of which show promise.

Trofinetide. One of the most promising targets for downstream therapy, mentioned earlier, is IGF-1, which was the target of a successful phase 3 clinical trial, LAVENDER (sponsored by Acadia Pharmaceuticals).^35,36 This trial studied trofinetide, a synthetic IGF-1 analog that inhibits neuroinflammation, restores glial function, corrects synaptic deficiencies, and regulates oxidative stress response.^12,37,38 Initial results from phase 2 and phase 3 trials indicate improved scores for treated patients in the Rett syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression–Improvement (CGI-I) scores, while also showing improvements in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist–Social composite score.^36,39

The most common adverse events seen with trofinetide were diarrhea and vomiting.

Acadia Pharmaceuticals has filed for approval of a new drug application for trofinetide with the Food and Drug Administration, for which the company has been granted Fast Track Status and orphan drug designations. Most (95%) subjects in the phase 3 LAVENDER trial elected to continue taking trofinetide in the subsequent open-label Lilac and Lilac-2 extension studies.³⁶ A current open-label phase 2/3 trial is recruiting patients 2 to 5 years of age to evaluate trofinetide.⁴⁰ It is expected that, in the near future, this could be a drug given to Rett patients as an FDA-approved treatment.

Blarcamesine. Another small molecule drug, blarcamesine (also known as ANAVEX2-73), a sigma-1 receptor agonist, produced promising results in phase 2 clinical trials in adult Rett syndrome patients. The drug is in a phase 2/3 clinical trial for pediatric Rett syndrome patients (sponsored by Anavex Life Sciences).^41-43

Phase 2 results indicated statistically significant and clinically meaningful improvement in RSBQ and CGI-I scores with blarcamesine. Improvement was initially observed within 4 weeks after the start of treatment and was sustained throughout the study. The drug was shown to be well tolerated, with minimal adverse effects; no serious adverse events were recorded. These results were observed in adult patients, demonstrating that improvements in Rett syndrome are possible even after regression.

Blarcamesine activates the sigma 1 receptor, which is pivotal to restoring cellular homeostasis and restoring neuroplasticity – deficiencies of which have been linked to autophagy and glutamate toxicity. The drug has also been explored as a potential treatment for other neurological disorders.^44-47 Improvements in blarcamesine-treated patients further correlated with lower levels of glutamate in cerebrospinal fluid, which is a Rett syndrome biomarker, supporting the proposition that behavioral improvements were due to drug intervention.^48,49 The phase 2 trial was modified into a phase 3 trial and additional endpoints were added.^41-43

All patients in the phase 2 adult trial elected to continue in the extension study.

Based on these promising data, Anavex is pursuing an approval pathway for adult patients, while continuing dosage optimization phase 2/3 trials and recruitment for a pediatric trial.^42,43

Is the future about gene therapy?

TSHA-102 (miniMECP2). Taysha Gene Therapies is developing a promising gene therapy, TSHA-102, for Rett syndrome, and is aiming to begin phase 1/2 clinical trials in 2022.⁵⁰ The technology for this therapy relies on the delivery of a fragment of MECP2 (known as miniMECP2), which is regulated by a built-in microRNA regulator (miR-responsive auto-regulatory element, or miRARE) to help ameliorate MECP2 dosage toxicity. (Overexpression of MECP2 is toxic to neurons, which has made traditional [so to speak] gene replacement therapy difficult in Rett syndrome: Levels of MECP2 need to be tightly regulated, and the Taysha microRNA technology regulates levels of miniMECP2, thus reducing toxicity.)

The Taysha microRNA technology has yielded promising results in mouse studies for Rett syndrome; results indicate a lengthening of lifespan and delayed onset of gait abnormalities.⁵¹ TSHA-102 is in the preclinical stage but offers promise that it will be the first gene therapy for Rett syndrome to enter clinical trials.

As the field of gene therapy advances, several promising technologies are on the horizon that could potentially have disease-altering impacts on Rett syndrome. These therapies are divided into two broad categories: those at the gene level and those at the transcription and protein level. A few of these approaches are highlighted below.

Gene replacement involves adding a full or partial copy of MECP2 to neuronal cells. This type of therapy presents challenges, from delivery of the new gene to dosage concerns, because MECP2 can be toxic if overexpressed.^52-54 Groundbreaking work was done in mouse models involving truncated MECP2, exhibiting phenotypic rescue and validating the gene-replacement approach.¹⁸ This strategy is being pursued by Neurogene, which has a uinique technology that allows for tuning of the gene’s expression to get the correct protein levels in the patient. Promising data was presented this year at the American Society of Gene and Cell Therapy conference.⁵⁵

Early gene replacement therapy studies also laid the foundation for the minMECP2 and microRNA approach being used by Taysha Gene Therapies (discussed above).⁵¹

“Correcting” DNA mutations. A different approach at the genetic level involves “correcting” mutations in MECP2 at the DNA level. This is possible because, in a large subset of Rett syndrome patients who have the same missense or nonsense mutations, by using CRISPR, a gene editing tool (discussed above) a single base pair can be corrected.^56,57 Previous research, in a Rett syndrome-model of induced pluripotent stem cells, showed that this type of editing is possible – and effective.⁵² An approach with particular promise involves use of a class of CRISPR proteins known as base editors that are able to specifically alter a single base of DNA.⁵⁷ The technique has the potential to address many of the mutations seen in Rett syndrome; research on this type of technology is being pursued by Beam Therapeutics, and has the potential to impact Rett syndrome.⁵⁸

Another promising “correction” approach is exonic editing, in which a much larger section of DNA – potentially, exons 3 and 4, which, taken together, comprise 97% of known MECP2 mutations seen in Rett syndrome – are replaced.⁵⁹

In both CRISPR and exonic editing therapeutic approaches, endogenous levels of MECP2 expression would be maintained. Of note, both approaches are being pursued for use in treating other genetic disorders, which provides a boost in scaling-up work on addressing safety and efficacy concerns that accompany gene-editing approaches.⁵⁸ One advantage to the DNA correction approach is that is has the potential to be a “one-and-done” treatment.

“Correcting” RNA. Beyond directly editing DNA, several therapeutic approaches are exploring the ability to edit RNA or to provide the protein directly to cells as enzyme replacement therapy. Such an RNA correction strategy leverages a technology that takes advantage of cells’ natural RNA editor, known as adenosine deaminase acting on RNA (ADAR), which corrects errors in cells’ RNA by providing specific guides to the cell. ADAR can be targeted to fix mutations in the MECP2 RNA transcript, resulting in a “corrected” MECP2 protein.^60,61 This technology has delivered promising proof-of-concept evidence in cells and in murine models, and is in the therapeutic pipeline at VICO Therapeutics.⁶²

• Leveraging internal repair mechanisms minimizes the immune response.
• The flexibility of correction means that it can be used to address many of the mutations that cause Rett syndrome.⁶³

Enzyme replacement therapy, in which the MECP2 protein produced by MECP2 would be directly replaced, is being explored in Rett syndrome patients. This technology has been used successfully in Pompe disease; however, Rett syndrome presents its own challenge because MECP2 needs to be delivered to the brain and neuronal cells.⁶⁴

Where does this work stand? The technologies described in this section are in preclinical stages of study. Nonetheless, it is expected that several will enter human clinical trials during the next 5 years.
 

Conclusion

A diagnosis of Rett syndrome is a life-altering event for patients and their family. But there is more hope than ever for effective therapies and, eventually, a cure.

Multiple late-stage clinical trials in progress are demonstrating promising results from therapeutic products, with minimal adverse events. Remarkably, these interventions have delivered improvements to adult patients after regression has stabilized. With rapid progress being made in the field of gene therapy, several technologies for which are focused on Rett syndrome, a hopeful picture is emerging: that therapeutic intervention will be possible before regression, thus effectively treating and, potentially, even curing Rett syndrome.

The landscape is broadening. Add to this hope for approved therapies is the fact that Rett syndrome isn’t the only target being pursued with such strategies; in fact, researchers in the larger field of neurodevelopmental disorder study are working together to find common solutions to shared challenges – from how therapies are designed and delivered to how toxicity is minimized. Much of what is being explored in the Rett syndrome field is also under investigation in other neurodevelopmental syndromes, including Angelman, Prader-Willi, chromosome 15q11.2-13.1 duplication (dup15q), and Fragile X syndrome. This kind of parallel investigation benefits all parties and optimizes a treatment platform so that it can be applied across more than a single disorder.

Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and vision, not just wide-eyed optimism. These words portend real promise for patients who carry the weight of a diagnosis of Rett syndrome, and for their families.
 

Ms. Ambrose is a student in the master’s of science in human genetics and genomic data analytics program, Keck Graduate Institute, Claremont, Calif. Dr. Bailus is an assistant professor of genetics, Keck Graduate Institute. The authors report no conflict of interest related to this article.

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39. Glaze DG et al; Rett 002 Study Group. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology. 2019 April 16;92(16):e1912-e1925. doi: 10.1212/WNL.0000000000007316.

40. Acadia Pharmaceuticals Inc. An open-label study of trofinetide for the treatment of girls two to five years of age who have Rett syndrome (DAFFODIL™). ClinicalTrials.gov Identifier: NCT04988867. Updated Jan 24, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04988867.

41. Anavex Life Sciences announces ANAVEX®2-73 meets primary and secondary endpoints in clinical trial. Press release. Anavex Life Sciences Corp. Dec 15, 2020. Accessed Feb 23, 2022. http://www.anavex.com/post/anavex-life-sciences-announces-anavex-2-73-meets-primary-and-secondary-endpoints-in-clinical-trial.

42. Anavex Life Sciences Corp. ANAVEX2-73 study in patients with Rett syndrome (AVATAR). ClinicalTrials.gov Identifier: NCT03941444. Updated Jan 27, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT03941444.

43. Anavex Life Sciences Corp. ANAVEX2-73 study in pediatric patients with Rett syndrome (EXCELLENCE). ClinicalTrials.gov Identifier: NCT04304482. Updated Sep 28, 2021. Accessed Feb 23, 2022. http://www.clinicaltrials.gov/ct2/show/NCT04304482.

44.Christ MG et al. The Sigma-1 receptor at the crossroad of proteostasis, neurodegeneration, and autophagy. Trends Neurosci. 2020 Feb;43(2):79-81. doi: 10.1016/j.tins.2019.12.002.

45. Kaufmann WE et al. ANAVEX®2-73 (blarcamesine), a sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome. Pharmacol Biochem Behav. 2019 Dec;187:172796. doi: 10.1016/j.pbb.2019.172796.

46. Brimson JM et al. Dipentylammonium binds to the sigma-1 receptor and protects against glutamate toxicity, attenuates dopamine toxicity and potentiates neurite outgrowth in various cultured cell lines. Neurotox Res. 2018 Aug;34(2):263-72. doi: 10.1007/s12640-018-9883-5.

47. Kourrich S et al. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci. 2012 Dec;35(12):762-71. doi: 10.1016/j.tins.2012.09.007.

48. Lappalainen R, Riikonen RS. High levels of cerebrospinal fluid glutamate in Rett syndrome. Pediatr Neurol. 1996 Oct;15(3):213-6. doi: 10.1016/s0887-8994(96)00218-4.

49. Hamberger A et al. Elevated CSF glutamate in Rett syndrome. Neuropediatrics. 1992;23(4):212-3. doi: 10.1055/s-2008-1071344.

50. Inacio P. FDA acts to support development of potential gene therapy, TSHA-102. Rett Syndrome News [Internet]. Oct 16, 2020. Accessed Feb 23, 2022. https://rettsyndromenews.com/2020/10/16/fda-grants-orphan-drug-rare-pediatric-disease-status-to-tsha-102-potential-rett-gene-therapy.

51. Sinnett SE et al. Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice. Brain. 2021 Nov 29;144(10):3005-19. doi: 10.1093/brain/awab182.

52. Le TTH et al. Efficient and precise CRISPR/Cas9-mediated MECP2 modifications in human-induced pluripotent stem cells. Front Genet. 2019 Jul 2;10:625. doi: 10.3389/fgene.2019.00625.

53. Koerner MV et al. Toxicity of overexpressed MeCP2 is independent of HDAC3 activity. Genes Dev. 2018;32(23-24):1514-24. doi: 10.1101/gad.320325.118.

54. Heckman LD et al. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife. 2014;3:e02676. doi: 10.7554/eLife.02676.

55. Neurogene announces new development program in Rett syndrome utilizing novel EXACT technology platform [Internet]. Accessed Aug 12, 2022. https://www.neurogene.com/press-releases/neurogene-announces-new-development-program-in-rett-syndrome-utilizing-novel-exact-technology-platform/

56. Anzalone AV et al. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020 Jul;38(7):824-44. doi: 10.1038/s41587-020-0561-9.

57. Gaudelli NM, Komor AC, Rees HA, et al. Programmable base editing of A●T to G●C in genomic DNA without DNA cleavage. Nature. 2017 Nov 23;551(7681):464-71. doi: 10.1038/nature24644.

58. Coenraads M. How RSRT is driving the search for a Rett cure. Rett Syndrome Research Trust [Internet]. Dec 7, 2021. Accessed Feb 23, 2022. https://rettnews.org/articles/how-rsrt-is-driving-the-search-for-a-rett-cure.

59. Cutting-edge technologies to repair the underlying mutations that cause Rett. Rett Syndrome Research Trust [Internet]. Updated Nov 3, 2021. Accessed Feb 23, 2022. https://reverserett.org/research/cures/gene-editing.

60. Sinnamon JR et al. In vivo repair of a protein underlying a neurological disorder by programmable RNA editing. Cell Rep. 2020 Jul 14;32(2):107878. doi: 10.1016/j.celrep.2020.107878.

61. Sinnamon JR et al. Site-directed RNA repair of endogenous Mecp2 RNA in neurons. Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9395-E9402. doi: 10.1073/pnas.1715320114.

62. Pipeline. VICO Therapeutics [Internet]. Updated Nov 5, 2021. Accessed Feb 23, 2022. https://vicotx.com/pipeline.

63. Therapeutics platform. Shape Therapeutics [Internet]. Updated Feb 20, 2021. Accessed Feb 23, 2022.

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64. Koeberl DD et al. Glycogen storage disease types I and II: Treatment updates. J Inherit Metab Dis. 2007 Apr;30(2):159-64. doi: 10.1007/s10545-007-0519-9.

The dream of curing genetic disorders has been a persistent but elusive goal, even before the human genome was mapped. Once mapping of the human genome was complete in 2001, an entirely new avenue of potential treatments and cures for genetic diseases and disorders was opened.^1,2

One of the rare monogenic disorders that is embracing multiple gene therapy approaches is Rett syndrome, a rare, debilitating neurodevelopmental disorder. In this review, we explore the molecular cause of Rett syndrome, disease presentation, current treatments, ongoing clinical trials, and therapies that are on the horizon.
 

Underlying molecular cause

Rett syndrome is caused by mutations in, or the absence of, the MECP2 gene, which produces methyl-CpG binding protein 2 (MECP2). The syndrome was first described clinically in 1954 by the Austrian physician Andreas Rett; it would take until 1982 before the disorder was officially named, eponymously, in a seminal paper by Hagberg.⁴ After Hagberg’s characterization, Rett syndrome became the predominant global clinical diagnosis identified among cognitively impaired females, with an incidence of 1 in every 10,000 to 15,000.⁴

In 1999, mutations in, and deletions of, MECP2 were identified as the cause of Rett syndrome.^4,5 MECP2 is located on the X chromosome, in the Xq28 region, making Rett syndrome an X-linked dominant disorder.⁶ Rett syndrome is seen predominantly in females who are mosaic for mutant or deleted MECP2. Random X chromosome inactivation results in some cells expressing the mutant MECP2 allele and other cells expressing the normal functioning MECP2 allele; the percentage of cells expressing the normal allele correlates with the degree of syndrome severity.^7-9

The incidence of Rett syndrome is much lower in males, in whom the syndrome was originally thought to be lethal; many observed male cases are either mosaic or occur in XXY males.^10,11

Approximately 95% of cases of Rett syndrome are due to de novo mutations in MECP2, with a handful of specific mutations and large deletions accounting for more than 85% of cases.¹² The fact that Rett syndrome is monogenic and most cases are caused by, in total, only a handful of mutations or deletions makes the syndrome a promising candidate for gene therapy.

At the molecular level, it has been observed that the MECP2 mutations of Rett syndrome lead to loss of gene function, thus disrupting the ability of the MECP2 nuclear protein to regulate global gene transcription through its binding to methylated DNA sites.¹² A large percentage of these missense and nonsense mutations lead to a truncated or nonfunctional protein.¹²

One of the ways in which MECP2 regulates transcription is as a component of heterochromatin condensates and by separation of heterochromatin and euchromatin.^13-15 It has been observed that the cells of Rett syndrome patients have an altered chromatin state, potentially contributing to transcriptional dysregulation.^16,17 Several mutations observed in Rett syndrome patients occur in crucial domains for heterochromatin condensate formation, which helps explain this cellular phenotype.¹³ Introduction of a engineered “mini” MECP2 in a murine model of Rett syndrome has resulted in partial rescue of heterochromatin condensate formation and transcriptional regulation – fostering the hypothesis that correcting those genetic changes could lead to a potential therapy.¹⁸

Beyond the role of MECP2 in heterochromatin condensate formation, the gene interacts with more than 40 proteins that have diverse roles in cellular function, epigenetic modulation, and neuronal development. This volume of interactions contributes to MECP2 being a global gene regulatory protein that has far-reaching effects on transcriptional regulation across the genome.^19-22

Epigenetic dysregulation has been associated with neurodevelopmental and neuropsychiatric disorders.²³ Both insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor are transcriptional targets of MECP2, and are involved in neuronal differentiation, synaptic function, and neurite outgrowth.¹² This helps explain the neurodevelopmental phenotypes observed in MECP2-mutated patients.

Notably, although Rett syndrome patients experience neurodevelopmental phenotypes at the cellular level, neuronal death is not readily observed. That observation provides hope that an interventional therapy after onset of symptoms might still be of benefit.
 

Presentation

Early neurotypical development. A hallmark of Rett syndrome is neurotypical physical and mental development until 6 to 24 months of age.

Stagnation is the first stage of the syndrome, involving a small but rapid decline in habitual milestones, such motor and language skills.¹² Subtle signs, such as microcephaly and hypotonia, can also arise at this time but might be missed.²⁴

Rapid regression follows stagnation. Speech and motor delays and impaired gait and breathing occur;^12,25 purposeful hand skills are lost, replaced by repetitive hand-wringing movements that are a hallmark of the syndrome.^12,24 Seizures are observed; they become more common during the next stage.¹²

Plateau. Language advances can be observed, but further deficits are seen in motor skills and hand coordination.¹²

Late motor deterioration stage. Late physical deficits develop, leading to lifelong impairments. The physical deficits observed are the result of severe muscle weakness, usually resulting in wheelchair dependency.¹²

Plateau. Patients then reach a second plateau. Regression stops; deficient physical and cognitive states stabilize and are maintained.²⁵

At all stages of Rett syndrome, the following are observed:

• Gastrointestinal problems.
• Sleep disturbances.
• Abnormal cardiorespiratory coupling.
• Greater-than-expected mortality.¹²

Final regression. The patient is fully dependent for the rest of their lifespan, partially due to seizure activity.^26,27
 

A life-changing diagnosis

A diagnosis of Rett syndrome is life-changing for a patient’s family; access to supportive groups of other patients and their families is extremely beneficial. Two helpful organizations – the Rett Syndrome Research Trust²⁸ and International Rett Syndrome Foundation,²⁹ – offer patient support and community and fund research.

Because X chromosome inactivation is random in Rett syndrome, the individual patient can present with a wide variety of phenotypic combinations – making the patient, and their needs, unique.¹² During stages of regression, patients often experience emotional dysregulation and anxiety, which is attributable to their increasing physical difficulties.³⁰ They often exhibit combinations of uncontrolled movements, including repetitive rocking, scratching, and self-injurious behavior.³⁰ For most, regression subsides after the first 5 years of alternating development and regression; after that, their ultimate symptoms persist for life.²⁵

As patients mature, they need to be monitored for proper nutrition and scoliosis.²⁵ As adults, they are at risk of pneumonia, respiratory distress, status epilepticus, osteopenia, and lack of adequate food or water because of impaired ability to feed.²⁵

The lifespan of Rett syndrome patients has increased, thanks to improvements in health care, advances in technology, and early genetic testing, which allows for earlier diagnosis, intervention, and management of symptoms.
 

Current treatments

When a female patient presents with regression and loss of milestones, sequencing of MECP2 is performed to verify whether Rett syndrome is the cause, by detecting any of the known mutations. Multiplex ligation-dependent probe amplification is also performed to detect major deletions.²⁵

All available treatments for Rett syndrome are symptomatic; intensive early intervention is practiced.³¹ Multidisciplinary management – medical, psychiatric, and physical – is introduced almost immediately after diagnosis. Following diagnosis, patients are prescribed anti-seizure, sleep, and anxiety medications.³¹ Electroencephalography can be performed to identify seizure type. Neuromuscular blockage drugs can be prescribed to help with gait and stereotypic hand movements.²⁵

Handguards or splints to the elbows can be prescribed by an occupational therapist to improve hand movement.²⁵ Physical therapy can improve mobility; hydrotherapy and hippotherapy have been successful in helping to maintain mobility and muscle support.^32,33 Nutritional management is implemented to control caloric intake and maintain the vitamin D level.³¹ Some patients experience constipation and urinary retention, putting them at risk of nephrolithiasis.

Once the signs and symptoms of Rett syndrome progress, and milestones regress to a certain point, patients need constant, full-time care for the rest of their lives.³⁴ As symptomatic interventions have greatly improved patient outcomes and it has been shown that about 70% can reach adulthood with a potential lifespan of about 50 years.²⁵

Although there is no cure for Rett syndrome and treatments are symptomatic, ongoing studies – both clinical and preclinical – offer promise that treatments will be developed that work at molecular and genetic levels.
 

Clinical trials

Advances in understanding of Rett syndrome have led to many therapies in clinical trials, several of which show promise.

Trofinetide. One of the most promising targets for downstream therapy, mentioned earlier, is IGF-1, which was the target of a successful phase 3 clinical trial, LAVENDER (sponsored by Acadia Pharmaceuticals).^35,36 This trial studied trofinetide, a synthetic IGF-1 analog that inhibits neuroinflammation, restores glial function, corrects synaptic deficiencies, and regulates oxidative stress response.^12,37,38 Initial results from phase 2 and phase 3 trials indicate improved scores for treated patients in the Rett syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression–Improvement (CGI-I) scores, while also showing improvements in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist–Social composite score.^36,39

The most common adverse events seen with trofinetide were diarrhea and vomiting.

Acadia Pharmaceuticals has filed for approval of a new drug application for trofinetide with the Food and Drug Administration, for which the company has been granted Fast Track Status and orphan drug designations. Most (95%) subjects in the phase 3 LAVENDER trial elected to continue taking trofinetide in the subsequent open-label Lilac and Lilac-2 extension studies.³⁶ A current open-label phase 2/3 trial is recruiting patients 2 to 5 years of age to evaluate trofinetide.⁴⁰ It is expected that, in the near future, this could be a drug given to Rett patients as an FDA-approved treatment.

Blarcamesine. Another small molecule drug, blarcamesine (also known as ANAVEX2-73), a sigma-1 receptor agonist, produced promising results in phase 2 clinical trials in adult Rett syndrome patients. The drug is in a phase 2/3 clinical trial for pediatric Rett syndrome patients (sponsored by Anavex Life Sciences).^41-43

Phase 2 results indicated statistically significant and clinically meaningful improvement in RSBQ and CGI-I scores with blarcamesine. Improvement was initially observed within 4 weeks after the start of treatment and was sustained throughout the study. The drug was shown to be well tolerated, with minimal adverse effects; no serious adverse events were recorded. These results were observed in adult patients, demonstrating that improvements in Rett syndrome are possible even after regression.

Blarcamesine activates the sigma 1 receptor, which is pivotal to restoring cellular homeostasis and restoring neuroplasticity – deficiencies of which have been linked to autophagy and glutamate toxicity. The drug has also been explored as a potential treatment for other neurological disorders.^44-47 Improvements in blarcamesine-treated patients further correlated with lower levels of glutamate in cerebrospinal fluid, which is a Rett syndrome biomarker, supporting the proposition that behavioral improvements were due to drug intervention.^48,49 The phase 2 trial was modified into a phase 3 trial and additional endpoints were added.^41-43

All patients in the phase 2 adult trial elected to continue in the extension study.

Based on these promising data, Anavex is pursuing an approval pathway for adult patients, while continuing dosage optimization phase 2/3 trials and recruitment for a pediatric trial.^42,43

Is the future about gene therapy?

TSHA-102 (miniMECP2). Taysha Gene Therapies is developing a promising gene therapy, TSHA-102, for Rett syndrome, and is aiming to begin phase 1/2 clinical trials in 2022.⁵⁰ The technology for this therapy relies on the delivery of a fragment of MECP2 (known as miniMECP2), which is regulated by a built-in microRNA regulator (miR-responsive auto-regulatory element, or miRARE) to help ameliorate MECP2 dosage toxicity. (Overexpression of MECP2 is toxic to neurons, which has made traditional [so to speak] gene replacement therapy difficult in Rett syndrome: Levels of MECP2 need to be tightly regulated, and the Taysha microRNA technology regulates levels of miniMECP2, thus reducing toxicity.)

The Taysha microRNA technology has yielded promising results in mouse studies for Rett syndrome; results indicate a lengthening of lifespan and delayed onset of gait abnormalities.⁵¹ TSHA-102 is in the preclinical stage but offers promise that it will be the first gene therapy for Rett syndrome to enter clinical trials.

As the field of gene therapy advances, several promising technologies are on the horizon that could potentially have disease-altering impacts on Rett syndrome. These therapies are divided into two broad categories: those at the gene level and those at the transcription and protein level. A few of these approaches are highlighted below.

Gene replacement involves adding a full or partial copy of MECP2 to neuronal cells. This type of therapy presents challenges, from delivery of the new gene to dosage concerns, because MECP2 can be toxic if overexpressed.^52-54 Groundbreaking work was done in mouse models involving truncated MECP2, exhibiting phenotypic rescue and validating the gene-replacement approach.¹⁸ This strategy is being pursued by Neurogene, which has a uinique technology that allows for tuning of the gene’s expression to get the correct protein levels in the patient. Promising data was presented this year at the American Society of Gene and Cell Therapy conference.⁵⁵

Early gene replacement therapy studies also laid the foundation for the minMECP2 and microRNA approach being used by Taysha Gene Therapies (discussed above).⁵¹

“Correcting” DNA mutations. A different approach at the genetic level involves “correcting” mutations in MECP2 at the DNA level. This is possible because, in a large subset of Rett syndrome patients who have the same missense or nonsense mutations, by using CRISPR, a gene editing tool (discussed above) a single base pair can be corrected.^56,57 Previous research, in a Rett syndrome-model of induced pluripotent stem cells, showed that this type of editing is possible – and effective.⁵² An approach with particular promise involves use of a class of CRISPR proteins known as base editors that are able to specifically alter a single base of DNA.⁵⁷ The technique has the potential to address many of the mutations seen in Rett syndrome; research on this type of technology is being pursued by Beam Therapeutics, and has the potential to impact Rett syndrome.⁵⁸

Another promising “correction” approach is exonic editing, in which a much larger section of DNA – potentially, exons 3 and 4, which, taken together, comprise 97% of known MECP2 mutations seen in Rett syndrome – are replaced.⁵⁹

In both CRISPR and exonic editing therapeutic approaches, endogenous levels of MECP2 expression would be maintained. Of note, both approaches are being pursued for use in treating other genetic disorders, which provides a boost in scaling-up work on addressing safety and efficacy concerns that accompany gene-editing approaches.⁵⁸ One advantage to the DNA correction approach is that is has the potential to be a “one-and-done” treatment.

“Correcting” RNA. Beyond directly editing DNA, several therapeutic approaches are exploring the ability to edit RNA or to provide the protein directly to cells as enzyme replacement therapy. Such an RNA correction strategy leverages a technology that takes advantage of cells’ natural RNA editor, known as adenosine deaminase acting on RNA (ADAR), which corrects errors in cells’ RNA by providing specific guides to the cell. ADAR can be targeted to fix mutations in the MECP2 RNA transcript, resulting in a “corrected” MECP2 protein.^60,61 This technology has delivered promising proof-of-concept evidence in cells and in murine models, and is in the therapeutic pipeline at VICO Therapeutics.⁶²

• Leveraging internal repair mechanisms minimizes the immune response.
• The flexibility of correction means that it can be used to address many of the mutations that cause Rett syndrome.⁶³

Enzyme replacement therapy, in which the MECP2 protein produced by MECP2 would be directly replaced, is being explored in Rett syndrome patients. This technology has been used successfully in Pompe disease; however, Rett syndrome presents its own challenge because MECP2 needs to be delivered to the brain and neuronal cells.⁶⁴

Where does this work stand? The technologies described in this section are in preclinical stages of study. Nonetheless, it is expected that several will enter human clinical trials during the next 5 years.
 

Conclusion

A diagnosis of Rett syndrome is a life-altering event for patients and their family. But there is more hope than ever for effective therapies and, eventually, a cure.

Multiple late-stage clinical trials in progress are demonstrating promising results from therapeutic products, with minimal adverse events. Remarkably, these interventions have delivered improvements to adult patients after regression has stabilized. With rapid progress being made in the field of gene therapy, several technologies for which are focused on Rett syndrome, a hopeful picture is emerging: that therapeutic intervention will be possible before regression, thus effectively treating and, potentially, even curing Rett syndrome.

The landscape is broadening. Add to this hope for approved therapies is the fact that Rett syndrome isn’t the only target being pursued with such strategies; in fact, researchers in the larger field of neurodevelopmental disorder study are working together to find common solutions to shared challenges – from how therapies are designed and delivered to how toxicity is minimized. Much of what is being explored in the Rett syndrome field is also under investigation in other neurodevelopmental syndromes, including Angelman, Prader-Willi, chromosome 15q11.2-13.1 duplication (dup15q), and Fragile X syndrome. This kind of parallel investigation benefits all parties and optimizes a treatment platform so that it can be applied across more than a single disorder.

Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and vision, not just wide-eyed optimism. These words portend real promise for patients who carry the weight of a diagnosis of Rett syndrome, and for their families.
 

Ms. Ambrose is a student in the master’s of science in human genetics and genomic data analytics program, Keck Graduate Institute, Claremont, Calif. Dr. Bailus is an assistant professor of genetics, Keck Graduate Institute. The authors report no conflict of interest related to this article.

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36. Acadia Pharmaceuticals announces positive top-line results from the pivotal phase 3 LAVENDER trial of trofinetide in Rett syndrome. Press release. Acadia Pharmaceuticals Inc. Dec 6, 2021. Accessed Feb 23, 2022. https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-positive-top-line-results-1.

37. Copping NA et al. Emerging gene and small molecule therapies for the neurodevelopmental disorder Angelman syndrome. Neurotherapeutics. 2021 Jul;18(3):1535-47. doi: 10.1007/s13311-021-01082-x.

38. Riikonen R. Insulin-like growth factors in the pathogenesis of neurological diseases in children. Int J Mol Sci. 2017 Sep;18(10):2056. doi: 10.3390/ijms18102056.

39. Glaze DG et al; Rett 002 Study Group. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology. 2019 April 16;92(16):e1912-e1925. doi: 10.1212/WNL.0000000000007316.

40. Acadia Pharmaceuticals Inc. An open-label study of trofinetide for the treatment of girls two to five years of age who have Rett syndrome (DAFFODIL™). ClinicalTrials.gov Identifier: NCT04988867. Updated Jan 24, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04988867.

41. Anavex Life Sciences announces ANAVEX®2-73 meets primary and secondary endpoints in clinical trial. Press release. Anavex Life Sciences Corp. Dec 15, 2020. Accessed Feb 23, 2022. http://www.anavex.com/post/anavex-life-sciences-announces-anavex-2-73-meets-primary-and-secondary-endpoints-in-clinical-trial.

42. Anavex Life Sciences Corp. ANAVEX2-73 study in patients with Rett syndrome (AVATAR). ClinicalTrials.gov Identifier: NCT03941444. Updated Jan 27, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT03941444.

43. Anavex Life Sciences Corp. ANAVEX2-73 study in pediatric patients with Rett syndrome (EXCELLENCE). ClinicalTrials.gov Identifier: NCT04304482. Updated Sep 28, 2021. Accessed Feb 23, 2022. http://www.clinicaltrials.gov/ct2/show/NCT04304482.

44.Christ MG et al. The Sigma-1 receptor at the crossroad of proteostasis, neurodegeneration, and autophagy. Trends Neurosci. 2020 Feb;43(2):79-81. doi: 10.1016/j.tins.2019.12.002.

45. Kaufmann WE et al. ANAVEX®2-73 (blarcamesine), a sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome. Pharmacol Biochem Behav. 2019 Dec;187:172796. doi: 10.1016/j.pbb.2019.172796.

46. Brimson JM et al. Dipentylammonium binds to the sigma-1 receptor and protects against glutamate toxicity, attenuates dopamine toxicity and potentiates neurite outgrowth in various cultured cell lines. Neurotox Res. 2018 Aug;34(2):263-72. doi: 10.1007/s12640-018-9883-5.

47. Kourrich S et al. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci. 2012 Dec;35(12):762-71. doi: 10.1016/j.tins.2012.09.007.

48. Lappalainen R, Riikonen RS. High levels of cerebrospinal fluid glutamate in Rett syndrome. Pediatr Neurol. 1996 Oct;15(3):213-6. doi: 10.1016/s0887-8994(96)00218-4.

49. Hamberger A et al. Elevated CSF glutamate in Rett syndrome. Neuropediatrics. 1992;23(4):212-3. doi: 10.1055/s-2008-1071344.

50. Inacio P. FDA acts to support development of potential gene therapy, TSHA-102. Rett Syndrome News [Internet]. Oct 16, 2020. Accessed Feb 23, 2022. https://rettsyndromenews.com/2020/10/16/fda-grants-orphan-drug-rare-pediatric-disease-status-to-tsha-102-potential-rett-gene-therapy.

51. Sinnett SE et al. Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice. Brain. 2021 Nov 29;144(10):3005-19. doi: 10.1093/brain/awab182.

52. Le TTH et al. Efficient and precise CRISPR/Cas9-mediated MECP2 modifications in human-induced pluripotent stem cells. Front Genet. 2019 Jul 2;10:625. doi: 10.3389/fgene.2019.00625.

53. Koerner MV et al. Toxicity of overexpressed MeCP2 is independent of HDAC3 activity. Genes Dev. 2018;32(23-24):1514-24. doi: 10.1101/gad.320325.118.

54. Heckman LD et al. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife. 2014;3:e02676. doi: 10.7554/eLife.02676.

55. Neurogene announces new development program in Rett syndrome utilizing novel EXACT technology platform [Internet]. Accessed Aug 12, 2022. https://www.neurogene.com/press-releases/neurogene-announces-new-development-program-in-rett-syndrome-utilizing-novel-exact-technology-platform/

56. Anzalone AV et al. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020 Jul;38(7):824-44. doi: 10.1038/s41587-020-0561-9.

57. Gaudelli NM, Komor AC, Rees HA, et al. Programmable base editing of A●T to G●C in genomic DNA without DNA cleavage. Nature. 2017 Nov 23;551(7681):464-71. doi: 10.1038/nature24644.

58. Coenraads M. How RSRT is driving the search for a Rett cure. Rett Syndrome Research Trust [Internet]. Dec 7, 2021. Accessed Feb 23, 2022. https://rettnews.org/articles/how-rsrt-is-driving-the-search-for-a-rett-cure.

59. Cutting-edge technologies to repair the underlying mutations that cause Rett. Rett Syndrome Research Trust [Internet]. Updated Nov 3, 2021. Accessed Feb 23, 2022. https://reverserett.org/research/cures/gene-editing.

60. Sinnamon JR et al. In vivo repair of a protein underlying a neurological disorder by programmable RNA editing. Cell Rep. 2020 Jul 14;32(2):107878. doi: 10.1016/j.celrep.2020.107878.

61. Sinnamon JR et al. Site-directed RNA repair of endogenous Mecp2 RNA in neurons. Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9395-E9402. doi: 10.1073/pnas.1715320114.

62. Pipeline. VICO Therapeutics [Internet]. Updated Nov 5, 2021. Accessed Feb 23, 2022. https://vicotx.com/pipeline.

63. Therapeutics platform. Shape Therapeutics [Internet]. Updated Feb 20, 2021. Accessed Feb 23, 2022.

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64. Koeberl DD et al. Glycogen storage disease types I and II: Treatment updates. J Inherit Metab Dis. 2007 Apr;30(2):159-64. doi: 10.1007/s10545-007-0519-9.

The dream of curing genetic disorders has been a persistent but elusive goal, even before the human genome was mapped. Once mapping of the human genome was complete in 2001, an entirely new avenue of potential treatments and cures for genetic diseases and disorders was opened.^1,2

One of the rare monogenic disorders that is embracing multiple gene therapy approaches is Rett syndrome, a rare, debilitating neurodevelopmental disorder. In this review, we explore the molecular cause of Rett syndrome, disease presentation, current treatments, ongoing clinical trials, and therapies that are on the horizon.
 

Underlying molecular cause

Rett syndrome is caused by mutations in, or the absence of, the MECP2 gene, which produces methyl-CpG binding protein 2 (MECP2). The syndrome was first described clinically in 1954 by the Austrian physician Andreas Rett; it would take until 1982 before the disorder was officially named, eponymously, in a seminal paper by Hagberg.⁴ After Hagberg’s characterization, Rett syndrome became the predominant global clinical diagnosis identified among cognitively impaired females, with an incidence of 1 in every 10,000 to 15,000.⁴

In 1999, mutations in, and deletions of, MECP2 were identified as the cause of Rett syndrome.^4,5 MECP2 is located on the X chromosome, in the Xq28 region, making Rett syndrome an X-linked dominant disorder.⁶ Rett syndrome is seen predominantly in females who are mosaic for mutant or deleted MECP2. Random X chromosome inactivation results in some cells expressing the mutant MECP2 allele and other cells expressing the normal functioning MECP2 allele; the percentage of cells expressing the normal allele correlates with the degree of syndrome severity.^7-9

The incidence of Rett syndrome is much lower in males, in whom the syndrome was originally thought to be lethal; many observed male cases are either mosaic or occur in XXY males.^10,11

Approximately 95% of cases of Rett syndrome are due to de novo mutations in MECP2, with a handful of specific mutations and large deletions accounting for more than 85% of cases.¹² The fact that Rett syndrome is monogenic and most cases are caused by, in total, only a handful of mutations or deletions makes the syndrome a promising candidate for gene therapy.

At the molecular level, it has been observed that the MECP2 mutations of Rett syndrome lead to loss of gene function, thus disrupting the ability of the MECP2 nuclear protein to regulate global gene transcription through its binding to methylated DNA sites.¹² A large percentage of these missense and nonsense mutations lead to a truncated or nonfunctional protein.¹²

One of the ways in which MECP2 regulates transcription is as a component of heterochromatin condensates and by separation of heterochromatin and euchromatin.^13-15 It has been observed that the cells of Rett syndrome patients have an altered chromatin state, potentially contributing to transcriptional dysregulation.^16,17 Several mutations observed in Rett syndrome patients occur in crucial domains for heterochromatin condensate formation, which helps explain this cellular phenotype.¹³ Introduction of a engineered “mini” MECP2 in a murine model of Rett syndrome has resulted in partial rescue of heterochromatin condensate formation and transcriptional regulation – fostering the hypothesis that correcting those genetic changes could lead to a potential therapy.¹⁸

Beyond the role of MECP2 in heterochromatin condensate formation, the gene interacts with more than 40 proteins that have diverse roles in cellular function, epigenetic modulation, and neuronal development. This volume of interactions contributes to MECP2 being a global gene regulatory protein that has far-reaching effects on transcriptional regulation across the genome.^19-22

Epigenetic dysregulation has been associated with neurodevelopmental and neuropsychiatric disorders.²³ Both insulin-like growth factor 1 (IGF-1) and brain-derived neurotrophic factor are transcriptional targets of MECP2, and are involved in neuronal differentiation, synaptic function, and neurite outgrowth.¹² This helps explain the neurodevelopmental phenotypes observed in MECP2-mutated patients.

Notably, although Rett syndrome patients experience neurodevelopmental phenotypes at the cellular level, neuronal death is not readily observed. That observation provides hope that an interventional therapy after onset of symptoms might still be of benefit.
 

Presentation

Early neurotypical development. A hallmark of Rett syndrome is neurotypical physical and mental development until 6 to 24 months of age.

Stagnation is the first stage of the syndrome, involving a small but rapid decline in habitual milestones, such motor and language skills.¹² Subtle signs, such as microcephaly and hypotonia, can also arise at this time but might be missed.²⁴

Rapid regression follows stagnation. Speech and motor delays and impaired gait and breathing occur;^12,25 purposeful hand skills are lost, replaced by repetitive hand-wringing movements that are a hallmark of the syndrome.^12,24 Seizures are observed; they become more common during the next stage.¹²

Plateau. Language advances can be observed, but further deficits are seen in motor skills and hand coordination.¹²

Late motor deterioration stage. Late physical deficits develop, leading to lifelong impairments. The physical deficits observed are the result of severe muscle weakness, usually resulting in wheelchair dependency.¹²

Plateau. Patients then reach a second plateau. Regression stops; deficient physical and cognitive states stabilize and are maintained.²⁵

At all stages of Rett syndrome, the following are observed:

• Gastrointestinal problems.
• Sleep disturbances.
• Abnormal cardiorespiratory coupling.
• Greater-than-expected mortality.¹²

Final regression. The patient is fully dependent for the rest of their lifespan, partially due to seizure activity.^26,27
 

A life-changing diagnosis

A diagnosis of Rett syndrome is life-changing for a patient’s family; access to supportive groups of other patients and their families is extremely beneficial. Two helpful organizations – the Rett Syndrome Research Trust²⁸ and International Rett Syndrome Foundation,²⁹ – offer patient support and community and fund research.

Because X chromosome inactivation is random in Rett syndrome, the individual patient can present with a wide variety of phenotypic combinations – making the patient, and their needs, unique.¹² During stages of regression, patients often experience emotional dysregulation and anxiety, which is attributable to their increasing physical difficulties.³⁰ They often exhibit combinations of uncontrolled movements, including repetitive rocking, scratching, and self-injurious behavior.³⁰ For most, regression subsides after the first 5 years of alternating development and regression; after that, their ultimate symptoms persist for life.²⁵

As patients mature, they need to be monitored for proper nutrition and scoliosis.²⁵ As adults, they are at risk of pneumonia, respiratory distress, status epilepticus, osteopenia, and lack of adequate food or water because of impaired ability to feed.²⁵

The lifespan of Rett syndrome patients has increased, thanks to improvements in health care, advances in technology, and early genetic testing, which allows for earlier diagnosis, intervention, and management of symptoms.
 

Current treatments

When a female patient presents with regression and loss of milestones, sequencing of MECP2 is performed to verify whether Rett syndrome is the cause, by detecting any of the known mutations. Multiplex ligation-dependent probe amplification is also performed to detect major deletions.²⁵

All available treatments for Rett syndrome are symptomatic; intensive early intervention is practiced.³¹ Multidisciplinary management – medical, psychiatric, and physical – is introduced almost immediately after diagnosis. Following diagnosis, patients are prescribed anti-seizure, sleep, and anxiety medications.³¹ Electroencephalography can be performed to identify seizure type. Neuromuscular blockage drugs can be prescribed to help with gait and stereotypic hand movements.²⁵

Handguards or splints to the elbows can be prescribed by an occupational therapist to improve hand movement.²⁵ Physical therapy can improve mobility; hydrotherapy and hippotherapy have been successful in helping to maintain mobility and muscle support.^32,33 Nutritional management is implemented to control caloric intake and maintain the vitamin D level.³¹ Some patients experience constipation and urinary retention, putting them at risk of nephrolithiasis.

Once the signs and symptoms of Rett syndrome progress, and milestones regress to a certain point, patients need constant, full-time care for the rest of their lives.³⁴ As symptomatic interventions have greatly improved patient outcomes and it has been shown that about 70% can reach adulthood with a potential lifespan of about 50 years.²⁵

Although there is no cure for Rett syndrome and treatments are symptomatic, ongoing studies – both clinical and preclinical – offer promise that treatments will be developed that work at molecular and genetic levels.
 

Clinical trials

Advances in understanding of Rett syndrome have led to many therapies in clinical trials, several of which show promise.

Trofinetide. One of the most promising targets for downstream therapy, mentioned earlier, is IGF-1, which was the target of a successful phase 3 clinical trial, LAVENDER (sponsored by Acadia Pharmaceuticals).^35,36 This trial studied trofinetide, a synthetic IGF-1 analog that inhibits neuroinflammation, restores glial function, corrects synaptic deficiencies, and regulates oxidative stress response.^12,37,38 Initial results from phase 2 and phase 3 trials indicate improved scores for treated patients in the Rett syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression–Improvement (CGI-I) scores, while also showing improvements in the Communication and Symbolic Behavior Scales Developmental Profile Infant–Toddler Checklist–Social composite score.^36,39

The most common adverse events seen with trofinetide were diarrhea and vomiting.

Acadia Pharmaceuticals has filed for approval of a new drug application for trofinetide with the Food and Drug Administration, for which the company has been granted Fast Track Status and orphan drug designations. Most (95%) subjects in the phase 3 LAVENDER trial elected to continue taking trofinetide in the subsequent open-label Lilac and Lilac-2 extension studies.³⁶ A current open-label phase 2/3 trial is recruiting patients 2 to 5 years of age to evaluate trofinetide.⁴⁰ It is expected that, in the near future, this could be a drug given to Rett patients as an FDA-approved treatment.

Blarcamesine. Another small molecule drug, blarcamesine (also known as ANAVEX2-73), a sigma-1 receptor agonist, produced promising results in phase 2 clinical trials in adult Rett syndrome patients. The drug is in a phase 2/3 clinical trial for pediatric Rett syndrome patients (sponsored by Anavex Life Sciences).^41-43

Phase 2 results indicated statistically significant and clinically meaningful improvement in RSBQ and CGI-I scores with blarcamesine. Improvement was initially observed within 4 weeks after the start of treatment and was sustained throughout the study. The drug was shown to be well tolerated, with minimal adverse effects; no serious adverse events were recorded. These results were observed in adult patients, demonstrating that improvements in Rett syndrome are possible even after regression.

Blarcamesine activates the sigma 1 receptor, which is pivotal to restoring cellular homeostasis and restoring neuroplasticity – deficiencies of which have been linked to autophagy and glutamate toxicity. The drug has also been explored as a potential treatment for other neurological disorders.^44-47 Improvements in blarcamesine-treated patients further correlated with lower levels of glutamate in cerebrospinal fluid, which is a Rett syndrome biomarker, supporting the proposition that behavioral improvements were due to drug intervention.^48,49 The phase 2 trial was modified into a phase 3 trial and additional endpoints were added.^41-43

All patients in the phase 2 adult trial elected to continue in the extension study.

Based on these promising data, Anavex is pursuing an approval pathway for adult patients, while continuing dosage optimization phase 2/3 trials and recruitment for a pediatric trial.^42,43

Is the future about gene therapy?

TSHA-102 (miniMECP2). Taysha Gene Therapies is developing a promising gene therapy, TSHA-102, for Rett syndrome, and is aiming to begin phase 1/2 clinical trials in 2022.⁵⁰ The technology for this therapy relies on the delivery of a fragment of MECP2 (known as miniMECP2), which is regulated by a built-in microRNA regulator (miR-responsive auto-regulatory element, or miRARE) to help ameliorate MECP2 dosage toxicity. (Overexpression of MECP2 is toxic to neurons, which has made traditional [so to speak] gene replacement therapy difficult in Rett syndrome: Levels of MECP2 need to be tightly regulated, and the Taysha microRNA technology regulates levels of miniMECP2, thus reducing toxicity.)

The Taysha microRNA technology has yielded promising results in mouse studies for Rett syndrome; results indicate a lengthening of lifespan and delayed onset of gait abnormalities.⁵¹ TSHA-102 is in the preclinical stage but offers promise that it will be the first gene therapy for Rett syndrome to enter clinical trials.

As the field of gene therapy advances, several promising technologies are on the horizon that could potentially have disease-altering impacts on Rett syndrome. These therapies are divided into two broad categories: those at the gene level and those at the transcription and protein level. A few of these approaches are highlighted below.

Gene replacement involves adding a full or partial copy of MECP2 to neuronal cells. This type of therapy presents challenges, from delivery of the new gene to dosage concerns, because MECP2 can be toxic if overexpressed.^52-54 Groundbreaking work was done in mouse models involving truncated MECP2, exhibiting phenotypic rescue and validating the gene-replacement approach.¹⁸ This strategy is being pursued by Neurogene, which has a uinique technology that allows for tuning of the gene’s expression to get the correct protein levels in the patient. Promising data was presented this year at the American Society of Gene and Cell Therapy conference.⁵⁵

Early gene replacement therapy studies also laid the foundation for the minMECP2 and microRNA approach being used by Taysha Gene Therapies (discussed above).⁵¹

“Correcting” DNA mutations. A different approach at the genetic level involves “correcting” mutations in MECP2 at the DNA level. This is possible because, in a large subset of Rett syndrome patients who have the same missense or nonsense mutations, by using CRISPR, a gene editing tool (discussed above) a single base pair can be corrected.^56,57 Previous research, in a Rett syndrome-model of induced pluripotent stem cells, showed that this type of editing is possible – and effective.⁵² An approach with particular promise involves use of a class of CRISPR proteins known as base editors that are able to specifically alter a single base of DNA.⁵⁷ The technique has the potential to address many of the mutations seen in Rett syndrome; research on this type of technology is being pursued by Beam Therapeutics, and has the potential to impact Rett syndrome.⁵⁸

Another promising “correction” approach is exonic editing, in which a much larger section of DNA – potentially, exons 3 and 4, which, taken together, comprise 97% of known MECP2 mutations seen in Rett syndrome – are replaced.⁵⁹

In both CRISPR and exonic editing therapeutic approaches, endogenous levels of MECP2 expression would be maintained. Of note, both approaches are being pursued for use in treating other genetic disorders, which provides a boost in scaling-up work on addressing safety and efficacy concerns that accompany gene-editing approaches.⁵⁸ One advantage to the DNA correction approach is that is has the potential to be a “one-and-done” treatment.

“Correcting” RNA. Beyond directly editing DNA, several therapeutic approaches are exploring the ability to edit RNA or to provide the protein directly to cells as enzyme replacement therapy. Such an RNA correction strategy leverages a technology that takes advantage of cells’ natural RNA editor, known as adenosine deaminase acting on RNA (ADAR), which corrects errors in cells’ RNA by providing specific guides to the cell. ADAR can be targeted to fix mutations in the MECP2 RNA transcript, resulting in a “corrected” MECP2 protein.^60,61 This technology has delivered promising proof-of-concept evidence in cells and in murine models, and is in the therapeutic pipeline at VICO Therapeutics.⁶²

• Leveraging internal repair mechanisms minimizes the immune response.
• The flexibility of correction means that it can be used to address many of the mutations that cause Rett syndrome.⁶³

Enzyme replacement therapy, in which the MECP2 protein produced by MECP2 would be directly replaced, is being explored in Rett syndrome patients. This technology has been used successfully in Pompe disease; however, Rett syndrome presents its own challenge because MECP2 needs to be delivered to the brain and neuronal cells.⁶⁴

Where does this work stand? The technologies described in this section are in preclinical stages of study. Nonetheless, it is expected that several will enter human clinical trials during the next 5 years.
 

Conclusion

A diagnosis of Rett syndrome is a life-altering event for patients and their family. But there is more hope than ever for effective therapies and, eventually, a cure.

Multiple late-stage clinical trials in progress are demonstrating promising results from therapeutic products, with minimal adverse events. Remarkably, these interventions have delivered improvements to adult patients after regression has stabilized. With rapid progress being made in the field of gene therapy, several technologies for which are focused on Rett syndrome, a hopeful picture is emerging: that therapeutic intervention will be possible before regression, thus effectively treating and, potentially, even curing Rett syndrome.

The landscape is broadening. Add to this hope for approved therapies is the fact that Rett syndrome isn’t the only target being pursued with such strategies; in fact, researchers in the larger field of neurodevelopmental disorder study are working together to find common solutions to shared challenges – from how therapies are designed and delivered to how toxicity is minimized. Much of what is being explored in the Rett syndrome field is also under investigation in other neurodevelopmental syndromes, including Angelman, Prader-Willi, chromosome 15q11.2-13.1 duplication (dup15q), and Fragile X syndrome. This kind of parallel investigation benefits all parties and optimizes a treatment platform so that it can be applied across more than a single disorder.

Like many monogenic disorders, Rett syndrome is entering an exciting stage – at which the words “treatment” and “cure” can be spoken with intent and vision, not just wide-eyed optimism. These words portend real promise for patients who carry the weight of a diagnosis of Rett syndrome, and for their families.
 

Ms. Ambrose is a student in the master’s of science in human genetics and genomic data analytics program, Keck Graduate Institute, Claremont, Calif. Dr. Bailus is an assistant professor of genetics, Keck Graduate Institute. The authors report no conflict of interest related to this article.

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33. Budden SS. Management of Rett syndrome: A ten year experience. Neuropediatrics. 1995;26(2):75-7. doi: 10.1055/s-2007-979727.

34. Ip JPK et al. Rett syndrome: Insights into genetic, molecular and circuit mechanisms. Nat Rev Neurosci. 2018 Jun;19(6):368-82. doi: 10.1038/s41583-018-0006-3.

35. Acadia Pharmaceuticals Inc. Study of trofinetide for the treatment of girls and women with Rett syndrome (LAVENDER™). ClinicalTrials.gov identifier: NCT04181723. Updated Feb 17, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04181723.

36. Acadia Pharmaceuticals announces positive top-line results from the pivotal phase 3 LAVENDER trial of trofinetide in Rett syndrome. Press release. Acadia Pharmaceuticals Inc. Dec 6, 2021. Accessed Feb 23, 2022. https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-positive-top-line-results-1.

37. Copping NA et al. Emerging gene and small molecule therapies for the neurodevelopmental disorder Angelman syndrome. Neurotherapeutics. 2021 Jul;18(3):1535-47. doi: 10.1007/s13311-021-01082-x.

38. Riikonen R. Insulin-like growth factors in the pathogenesis of neurological diseases in children. Int J Mol Sci. 2017 Sep;18(10):2056. doi: 10.3390/ijms18102056.

39. Glaze DG et al; Rett 002 Study Group. Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology. 2019 April 16;92(16):e1912-e1925. doi: 10.1212/WNL.0000000000007316.

40. Acadia Pharmaceuticals Inc. An open-label study of trofinetide for the treatment of girls two to five years of age who have Rett syndrome (DAFFODIL™). ClinicalTrials.gov Identifier: NCT04988867. Updated Jan 24, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04988867.

41. Anavex Life Sciences announces ANAVEX®2-73 meets primary and secondary endpoints in clinical trial. Press release. Anavex Life Sciences Corp. Dec 15, 2020. Accessed Feb 23, 2022. http://www.anavex.com/post/anavex-life-sciences-announces-anavex-2-73-meets-primary-and-secondary-endpoints-in-clinical-trial.

42. Anavex Life Sciences Corp. ANAVEX2-73 study in patients with Rett syndrome (AVATAR). ClinicalTrials.gov Identifier: NCT03941444. Updated Jan 27, 2022. Accessed Feb 23, 2022. https://clinicaltrials.gov/ct2/show/NCT03941444.

43. Anavex Life Sciences Corp. ANAVEX2-73 study in pediatric patients with Rett syndrome (EXCELLENCE). ClinicalTrials.gov Identifier: NCT04304482. Updated Sep 28, 2021. Accessed Feb 23, 2022. http://www.clinicaltrials.gov/ct2/show/NCT04304482.

44.Christ MG et al. The Sigma-1 receptor at the crossroad of proteostasis, neurodegeneration, and autophagy. Trends Neurosci. 2020 Feb;43(2):79-81. doi: 10.1016/j.tins.2019.12.002.

45. Kaufmann WE et al. ANAVEX®2-73 (blarcamesine), a sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome. Pharmacol Biochem Behav. 2019 Dec;187:172796. doi: 10.1016/j.pbb.2019.172796.

46. Brimson JM et al. Dipentylammonium binds to the sigma-1 receptor and protects against glutamate toxicity, attenuates dopamine toxicity and potentiates neurite outgrowth in various cultured cell lines. Neurotox Res. 2018 Aug;34(2):263-72. doi: 10.1007/s12640-018-9883-5.

47. Kourrich S et al. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends Neurosci. 2012 Dec;35(12):762-71. doi: 10.1016/j.tins.2012.09.007.

48. Lappalainen R, Riikonen RS. High levels of cerebrospinal fluid glutamate in Rett syndrome. Pediatr Neurol. 1996 Oct;15(3):213-6. doi: 10.1016/s0887-8994(96)00218-4.

49. Hamberger A et al. Elevated CSF glutamate in Rett syndrome. Neuropediatrics. 1992;23(4):212-3. doi: 10.1055/s-2008-1071344.

50. Inacio P. FDA acts to support development of potential gene therapy, TSHA-102. Rett Syndrome News [Internet]. Oct 16, 2020. Accessed Feb 23, 2022. https://rettsyndromenews.com/2020/10/16/fda-grants-orphan-drug-rare-pediatric-disease-status-to-tsha-102-potential-rett-gene-therapy.

51. Sinnett SE et al. Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice. Brain. 2021 Nov 29;144(10):3005-19. doi: 10.1093/brain/awab182.

52. Le TTH et al. Efficient and precise CRISPR/Cas9-mediated MECP2 modifications in human-induced pluripotent stem cells. Front Genet. 2019 Jul 2;10:625. doi: 10.3389/fgene.2019.00625.

53. Koerner MV et al. Toxicity of overexpressed MeCP2 is independent of HDAC3 activity. Genes Dev. 2018;32(23-24):1514-24. doi: 10.1101/gad.320325.118.

54. Heckman LD et al. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife. 2014;3:e02676. doi: 10.7554/eLife.02676.

55. Neurogene announces new development program in Rett syndrome utilizing novel EXACT technology platform [Internet]. Accessed Aug 12, 2022. https://www.neurogene.com/press-releases/neurogene-announces-new-development-program-in-rett-syndrome-utilizing-novel-exact-technology-platform/

56. Anzalone AV et al. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020 Jul;38(7):824-44. doi: 10.1038/s41587-020-0561-9.

57. Gaudelli NM, Komor AC, Rees HA, et al. Programmable base editing of A●T to G●C in genomic DNA without DNA cleavage. Nature. 2017 Nov 23;551(7681):464-71. doi: 10.1038/nature24644.

58. Coenraads M. How RSRT is driving the search for a Rett cure. Rett Syndrome Research Trust [Internet]. Dec 7, 2021. Accessed Feb 23, 2022. https://rettnews.org/articles/how-rsrt-is-driving-the-search-for-a-rett-cure.

59. Cutting-edge technologies to repair the underlying mutations that cause Rett. Rett Syndrome Research Trust [Internet]. Updated Nov 3, 2021. Accessed Feb 23, 2022. https://reverserett.org/research/cures/gene-editing.

60. Sinnamon JR et al. In vivo repair of a protein underlying a neurological disorder by programmable RNA editing. Cell Rep. 2020 Jul 14;32(2):107878. doi: 10.1016/j.celrep.2020.107878.

61. Sinnamon JR et al. Site-directed RNA repair of endogenous Mecp2 RNA in neurons. Proc Natl Acad Sci U S A. 2017 Oct 31;114(44):E9395-E9402. doi: 10.1073/pnas.1715320114.

62. Pipeline. VICO Therapeutics [Internet]. Updated Nov 5, 2021. Accessed Feb 23, 2022. https://vicotx.com/pipeline.

63. Therapeutics platform. Shape Therapeutics [Internet]. Updated Feb 20, 2021. Accessed Feb 23, 2022.

https://live-shapetx.pantheonsite.io/therapeutics-platform.

64. Koeberl DD et al. Glycogen storage disease types I and II: Treatment updates. J Inherit Metab Dis. 2007 Apr;30(2):159-64. doi: 10.1007/s10545-007-0519-9.

Until 2006, when a breakthrough therapy first made treatment possible, Pompe disease was a little-known metabolic myopathy fatal to infants. Those with later-onset disease experienced progressive, often severe disability into adulthood.

In this rare autosomal recessive disorder, which occurs in approximately one in 40,000 births worldwide, a deficiency or absence of the enzyme acid alpha-glucosidase causes glycogen to build up in the lysosomes of cells. While many tissues are affected, skeletal and cardiac muscle see the earliest involvement, with muscle hypotonia, cardiomyopathy, and breathing difficulties (mainly due to diaphragm weakness) comprising the hallmark symptoms of the infantile form. Muscle weakness and progressive respiratory failure are prominent in later-onset disease.

Diagnosis: Still room to improve

“Most neurologists will encounter a patient with Pompe disease,” said Dr. Kishnani, who has been working with Pompe for her entire career as a pediatrician and medical geneticist, treating patients of all ages and disease phenotypes.

“In newborns, diagnosis is more straightforward, because you’ve got an enlarged heart,” she said. And thanks to efforts of researchers like Dr. Kishnani and Pompe advocacy groups, Pompe disease is now a part of the RUSP (Recommended Uniform Screening Panel) for newborns; currently 28 U.S. states are screening for Pompe disease.

“The challenge really is for the later-onset cases, which are 80% of all cases,” Dr. Kishnani said.

Previously, muscle biopsies were the first step toward diagnosis. Dried blot spot assays to detect enzyme deficiency have since become the standard, along with other biochemical tests. Confirmation of the diagnosis is through gene sequencing panels to detect GAA mutations.

“Now that there is a treatment for Pompe disease and the availability of blood-based testing, many previously undiagnosed patients with limb girdle weakness are evaluated and the diagnostic odyssey ends,” Dr. Kishnani said. “But there is still a diagnostic delay, and many cases remain undiagnosed.”

Routine blood tests for creatine kinase and for liver enzymes can help point to Pompe disease. But elevated liver enzymes are often misinterpreted. “It’s about the ratios,” Dr. Kishnani said. “ALT is usually much more elevated if it is coming from a liver cause, and AST is usually higher than ALT if it is coming from muscle. But patients often end up getting a liver biopsy due to so-called elevated liver enzymes. As the workup continues, it is often later recognized that the source of the elevated enzymes is muscle involvement, and a referral to the geneticist or neurologist is made. Only then is appropriate testing to confirm a diagnosis initiated.”

Dr. Toscano, a neurologist who specializes in Pompe disease and other myopathies and who has published on tools for diagnosing late-onset Pompe disease,¹ said that clinicians should be vigilant when evaluating any patient with limb girdle weakness and elevated creatine kinase (CK) – “especially if the CK is under 2,000,” he said, “because it is very rare that patients with Pompe disease have a more elevated CK than that.”

“Elevated CK, myalgia, and exercise intolerance” should prompt clinicians to suspect Pompe disease in a patient of any age, Dr. Toscano said. “When you come across this, you should be very persistent and get to the end of the story.”

Dr. Toscano noted that the blood spot assay, while an important early step, is not fully diagnostic, “because you can have false positives.” The molecular GAA assay is used to confirm Pompe disease. But detecting pathogenic variants on the GAA gene – of which there are more than 500 – can be more complicated than it sounds. Whereas two mutations are required for Pompe disease, sometimes only one can be detected. Dr. Toscano said he also treated some patients for Pompe with only one known mutation but with unequivocal clinical and biochemical aspects of Pompe disease.

While delays in diagnosis for late-onset Pompe disease remain significant -- between 5 and 6 years on average for older patients, and up to 20 years for those with pediatric onset – both Dr. Kishnani and Dr. Toscano said they perceive them to be improving. With McArdle disease, another inherited glycogen storage disorder that is more common than Pompe disease but for which there is no treatment, “the delay is nearly 12 years,” Dr. Toscano said.
 

ERT: The sooner the better

Enzyme replacement therapy is indicated for all patients with Pompe disease. Currently two are commercially available: alglucosidase alfa (Lumizyme, Sanofi Genzyme), indicated for all forms of Pompe disease, and avalglucosidase alfa-ngpt (Nexviazyme, Sanofi Genzyme), approved in 2021 for later-onset Pompe, though its indications have yet to be fully defined.

The semimonthly infusions represent, to date, the only disease-modifying therapies commercially available. Enzyme replacement therapy can reverse cardiac damage seen in infants and allow them to meet developmental milestones previously unthinkable. In adults, it can slow progression, though many treated patients will still develop chronic disability and require a wheelchair, respiratory support, or both. “The phenotype of the patients we are seeing today is not as involved as it was prior to enzyme therapy,” said Dr. Kishnani, who was part of the research team that developed ERT and launched the first clinical trials. “This is across the disease spectrum.”

But optimal management means more than just getting a patient on therapy fast, Dr. Kishnani said.

“Very often the thinking is if the patient is on ERT, we’ve done right by the patient. Aspects we don’t look at enough include: Are we monitoring these patients well? Are patients being followed by a multidisciplinary team that includes cardiology, physical therapy, and pulmonary medicine? Are we doing appropriate musculoskeletal assessments? They might have sleep hypoventilation. The BiPap settings may not be correct. Or they have not been assessed for antibodies,” she said.

Many infants with severe phenotypes, notably those who produce no enzyme naturally, will develop immune reactions to the exogenous enzyme therapy. High antibody titers also have been seen and are associated with poor therapeutic response. While this is very clear in the infantile setting, late-onset patients also develop antibodies in response to ERT. In one study in 64 patients,² Dr. Toscano and his colleagues saw that antibodies may affect clinical response during the first 3 years of treatment, while a small study³ by Dr. Kishnani’s group saw clinical decline associated with high antibody titers in patients with late-onset disease.

While the relationship of specific titers to therapeutic response remains unclear, it is important to consider antibodies, along with other factors, in the monitoring of patients with Pompe disease. “We need to always ask, if a patient is falling behind, what could be the reason?” Dr. Kishnani said. “These are the things we as clinicians can do to improve or enhance the impact of ERT.”

Dr. Toscano noted that a common misconception about late-onset Pompe disease is that cardiac manifestations are minimal or absent, whereas as many as about 20% of patients will have heart problems and need to be carefully monitored.
 

Neurological manifestations

With patients surviving longer on ERT, researchers have been able to develop a deeper understanding of the natural history of Pompe disease. Increasingly, they are seeing it as a multisystem disease that includes central nervous system involvement.

“Is Pompe an overt neurodegenerative disease? I would say no,” Dr. Kishnani said. “But there is a neurological component that we’ve got to understand and follow more.”

Glycogen accumulation, she noted, has been found in anterior horn cells, motor neurons, and other parts of the brain. “We have been doing MRIs on children with infantile Pompe, and we have seen some white matter hyperintensities. The clinical significance of this finding is still emerging. Sometimes it is present, but the child is cognitively intact. We have had college graduates who have white matter hyperintensities. So putting it in context will be important. But we know that glycogen is ubiquitous, and autopsy studies have shown that it is present in the brain.”

In recent years, Dr. Toscano’s group has investigated neurovascular complications of Pompe in late-onset patients. “This was something that really surprised us because for several years we have investigated mainly heart, muscle, or respiratory manifestations of the disease, but the central nervous system was really neglected,” he said.

“Occasionally we did some brain MRIs and we found in even young patients some ischemic areas. We thought this was related to slowed circulation – that blood vessels in these patients are weak because they are impaired by glycogen accumulation.” Dr. Toscano and his colleagues followed that observation with a study of late-onset patients,⁴ in which they found that more than half had cerebrovascular abnormalities. “Even in, say, patients 30 to 35 years old we saw this – it’s unusual to have a vascular disorder at that age.”

Dr. Toscano and his colleagues also reported cerebral aneurysms⁵ in patients with Pompe disease and have recommended that clinicians conduct MRI or cerebral angiograms on patients as part of routine follow-up. Blood pressure in Pompe patients should be carefully watched and managed with antihypertensive medication as needed, he said.

Part of the problem is that the proteins in ERT are not able to cross the blood-brain barrier, Dr. Toscano noted, adding that researchers are investigating other treatments that can.
 

Pompe disease as a research model

The successful development of ERT for Pompe disease marked a boom in research interest into not just Pompe – for which several experimental therapies are currently in the pipeline – but for other myopathies and glycogen storage disorders.

“I think that Pompe has served as a template both as a muscle disease and a lysosomal storage disease, and so some of our learnings from Pompe have been applied across different diseases,” Dr. Kishnani said.

Studies in spinal muscular atrophy, for example, “in some ways mirrored what was done for Pompe – treatment trials were initiated in babies at the most severe end of the disease population with infantile disease, and used similar clinical trial endpoints,” Dr. Kishnani said. “Even for the later-onset end of the spectrum, the endpoints we used in Pompe for muscle strength and function have been relevant to many other neuromuscular disorders.”

Pompe disease research also ushered in a new appreciation of immune responses in protein replacement therapies, Dr. Kishnani noted.

“In the field today, you hear the term cross-reactive immunological material, or CRIM, all the time,” she said. “But when we first started talking about it in the space of Pompe disease, there was a lot of scientific debate about what the significance of CRIM-negative status was in relationship to the risk for development of high and sustained antibody titer and a poor clinical response. To understand this involved a lot of going back to the data and digging into the small subset of nonresponders. One of the powers of rare disease research is that every patient matters, and it’s important to understand what’s going on at the patient level rather than just the group data level.”
 

A robust pipeline

The decade and a half since the advent of ERT has seen what Dr. Toscano described as “an explosion of interest” in Pompe disease.

“We’re seeing an extraordinary number of papers on everything from clinical, biomarkers, genetics, and rehabilitation – this disease is now considered from every point of view, and this is very important for patients,” Dr. Toscano said. Alongside this has come industry interest in this rare disease, with several companies investigating a range of treatment approaches.

The existence of a treatment, “while not perfect,” he said, “has interested the patient associations and doctors to try and improve service to patients. Patients with Pompe disease are well attended, probably more so than patients with degenerative disorders in which there is no therapy.”

Last year the second ERT, avalglucosidase alfa (Nexviazyme, Sanofi Genzyme) was approved by the U.S. Food and Drug Administration to treat late-onset Pompe disease. The drug, currently being investigated in infants as well, was designed to improve the delivery of the therapeutic enzyme to muscles and enhance glycogen clearance, and results from ongoing trials suggest some functional and clinical benefit over standard ERT.

Other drugs in development for Pompe disease include substrate reduction therapies, which aim to reduce the storage of glycogen in cells, and therapies that improve residual function of mutant GAA enzyme in the body. These and other therapies in development have the potential to modify nervous system manifestations of Pompe disease.⁶

Because a single gene is implicated in Pompe disease, it has long been considered a good candidate for gene therapies that prompt the body to make stable enzyme. Seven companies are now investigating gene therapies in Pompe disease.⁷ Some of these deliver to skeletal muscles and others aim for the liver, where proteins are synthesized and secreted and adverse immune responses might be more easily mitigated. Other gene therapies use an ex vivo approach, removing and replacing cells in bone marrow.

Dr. Kishnani’s research group at Duke University is leading a small clinical trial in late-onset patients of a GAA gene transfer to the liver using adeno-associated virus (AAV) vectors.⁸

“We have started AAV gene therapy trials in in adults with Pompe disease and will later evaluate children because ERT is available as a standard of care, and so from a safety perspective this makes the most sense,” Dr. Kishnani said. “We do have challenges in the field of gene therapy, but I think if we are able to overcome the immune responses, and … to treat at a lower dose, there’s a very good pathway forward.”

Dr. Toscano and Dr. Kishnani have received reimbursement from Sanofi and other manufacturers for participation on advisory boards and as speakers.



Jennie Smith is a freelance journalist and editor specializing in medicine and health.

References

1. Musumeci O, Toscano A. Diagnostic tools in late onset Pompe disease (LOPD). Ann Transl Med. 2019 Jul;7(13):286. doi: 10.21037/atm.2019.06.60.

2. Filosto M et al. Assessing the role of anti rh-GAA in modulating response to ERT in a late-onset Pompe disease cohort from the Italian GSDII Study Group. Adv Ther. 2019 May;36(5):1177-1189. doi: 10.1007/s12325-019-00926-5.

3. Patel TT et al. The impact of antibodies in late-onset Pompe disease: A case series and literature review. Mol Genet Metab. 2012 Jul;106(3):301-9. doi: 10.1016/j.ymgme.2012.04.027.

4. Montagnese F et al. Intracranial arterial abnormalities in patients with late onset Pompe disease (LOPD). J Inherit Metab Dis. 2016 May;39(3):391-398. doi: 10.1007/s10545-015-9913-x.

5. Musumeci O et al. Central nervous system involvement in late-onset Pompe disease: Clues from neuroimaging and neuropsychological analysis. Eur J Neurol. 2019 Mar;26(3):442-e35. doi: 10.1111/ene.13835.

6. Edelmann MJ, Maegawa GHB. CNS-targeting therapies for lysosomal storage diseases: Current advances and challenges. Front Mol Biosci. 2020 Nov 12;7:559804. doi: 10.3389/fmolb.2020.559804

7. Ronzitti G et al. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):287. doi: 10.21037/atm.2019.04.67.

8. Kishnani PS, Koeberl DD. Liver depot gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):288. doi: 10.21037/atm.2019.05.02.

Until 2006, when a breakthrough therapy first made treatment possible, Pompe disease was a little-known metabolic myopathy fatal to infants. Those with later-onset disease experienced progressive, often severe disability into adulthood.

In this rare autosomal recessive disorder, which occurs in approximately one in 40,000 births worldwide, a deficiency or absence of the enzyme acid alpha-glucosidase causes glycogen to build up in the lysosomes of cells. While many tissues are affected, skeletal and cardiac muscle see the earliest involvement, with muscle hypotonia, cardiomyopathy, and breathing difficulties (mainly due to diaphragm weakness) comprising the hallmark symptoms of the infantile form. Muscle weakness and progressive respiratory failure are prominent in later-onset disease.

Diagnosis: Still room to improve

“Most neurologists will encounter a patient with Pompe disease,” said Dr. Kishnani, who has been working with Pompe for her entire career as a pediatrician and medical geneticist, treating patients of all ages and disease phenotypes.

“In newborns, diagnosis is more straightforward, because you’ve got an enlarged heart,” she said. And thanks to efforts of researchers like Dr. Kishnani and Pompe advocacy groups, Pompe disease is now a part of the RUSP (Recommended Uniform Screening Panel) for newborns; currently 28 U.S. states are screening for Pompe disease.

“The challenge really is for the later-onset cases, which are 80% of all cases,” Dr. Kishnani said.

Previously, muscle biopsies were the first step toward diagnosis. Dried blot spot assays to detect enzyme deficiency have since become the standard, along with other biochemical tests. Confirmation of the diagnosis is through gene sequencing panels to detect GAA mutations.

“Now that there is a treatment for Pompe disease and the availability of blood-based testing, many previously undiagnosed patients with limb girdle weakness are evaluated and the diagnostic odyssey ends,” Dr. Kishnani said. “But there is still a diagnostic delay, and many cases remain undiagnosed.”

Routine blood tests for creatine kinase and for liver enzymes can help point to Pompe disease. But elevated liver enzymes are often misinterpreted. “It’s about the ratios,” Dr. Kishnani said. “ALT is usually much more elevated if it is coming from a liver cause, and AST is usually higher than ALT if it is coming from muscle. But patients often end up getting a liver biopsy due to so-called elevated liver enzymes. As the workup continues, it is often later recognized that the source of the elevated enzymes is muscle involvement, and a referral to the geneticist or neurologist is made. Only then is appropriate testing to confirm a diagnosis initiated.”

Dr. Toscano, a neurologist who specializes in Pompe disease and other myopathies and who has published on tools for diagnosing late-onset Pompe disease,¹ said that clinicians should be vigilant when evaluating any patient with limb girdle weakness and elevated creatine kinase (CK) – “especially if the CK is under 2,000,” he said, “because it is very rare that patients with Pompe disease have a more elevated CK than that.”

“Elevated CK, myalgia, and exercise intolerance” should prompt clinicians to suspect Pompe disease in a patient of any age, Dr. Toscano said. “When you come across this, you should be very persistent and get to the end of the story.”

Dr. Toscano noted that the blood spot assay, while an important early step, is not fully diagnostic, “because you can have false positives.” The molecular GAA assay is used to confirm Pompe disease. But detecting pathogenic variants on the GAA gene – of which there are more than 500 – can be more complicated than it sounds. Whereas two mutations are required for Pompe disease, sometimes only one can be detected. Dr. Toscano said he also treated some patients for Pompe with only one known mutation but with unequivocal clinical and biochemical aspects of Pompe disease.

While delays in diagnosis for late-onset Pompe disease remain significant -- between 5 and 6 years on average for older patients, and up to 20 years for those with pediatric onset – both Dr. Kishnani and Dr. Toscano said they perceive them to be improving. With McArdle disease, another inherited glycogen storage disorder that is more common than Pompe disease but for which there is no treatment, “the delay is nearly 12 years,” Dr. Toscano said.
 

ERT: The sooner the better

Enzyme replacement therapy is indicated for all patients with Pompe disease. Currently two are commercially available: alglucosidase alfa (Lumizyme, Sanofi Genzyme), indicated for all forms of Pompe disease, and avalglucosidase alfa-ngpt (Nexviazyme, Sanofi Genzyme), approved in 2021 for later-onset Pompe, though its indications have yet to be fully defined.

The semimonthly infusions represent, to date, the only disease-modifying therapies commercially available. Enzyme replacement therapy can reverse cardiac damage seen in infants and allow them to meet developmental milestones previously unthinkable. In adults, it can slow progression, though many treated patients will still develop chronic disability and require a wheelchair, respiratory support, or both. “The phenotype of the patients we are seeing today is not as involved as it was prior to enzyme therapy,” said Dr. Kishnani, who was part of the research team that developed ERT and launched the first clinical trials. “This is across the disease spectrum.”

But optimal management means more than just getting a patient on therapy fast, Dr. Kishnani said.

“Very often the thinking is if the patient is on ERT, we’ve done right by the patient. Aspects we don’t look at enough include: Are we monitoring these patients well? Are patients being followed by a multidisciplinary team that includes cardiology, physical therapy, and pulmonary medicine? Are we doing appropriate musculoskeletal assessments? They might have sleep hypoventilation. The BiPap settings may not be correct. Or they have not been assessed for antibodies,” she said.

Many infants with severe phenotypes, notably those who produce no enzyme naturally, will develop immune reactions to the exogenous enzyme therapy. High antibody titers also have been seen and are associated with poor therapeutic response. While this is very clear in the infantile setting, late-onset patients also develop antibodies in response to ERT. In one study in 64 patients,² Dr. Toscano and his colleagues saw that antibodies may affect clinical response during the first 3 years of treatment, while a small study³ by Dr. Kishnani’s group saw clinical decline associated with high antibody titers in patients with late-onset disease.

While the relationship of specific titers to therapeutic response remains unclear, it is important to consider antibodies, along with other factors, in the monitoring of patients with Pompe disease. “We need to always ask, if a patient is falling behind, what could be the reason?” Dr. Kishnani said. “These are the things we as clinicians can do to improve or enhance the impact of ERT.”

Dr. Toscano noted that a common misconception about late-onset Pompe disease is that cardiac manifestations are minimal or absent, whereas as many as about 20% of patients will have heart problems and need to be carefully monitored.
 

Neurological manifestations

With patients surviving longer on ERT, researchers have been able to develop a deeper understanding of the natural history of Pompe disease. Increasingly, they are seeing it as a multisystem disease that includes central nervous system involvement.

“Is Pompe an overt neurodegenerative disease? I would say no,” Dr. Kishnani said. “But there is a neurological component that we’ve got to understand and follow more.”

Glycogen accumulation, she noted, has been found in anterior horn cells, motor neurons, and other parts of the brain. “We have been doing MRIs on children with infantile Pompe, and we have seen some white matter hyperintensities. The clinical significance of this finding is still emerging. Sometimes it is present, but the child is cognitively intact. We have had college graduates who have white matter hyperintensities. So putting it in context will be important. But we know that glycogen is ubiquitous, and autopsy studies have shown that it is present in the brain.”

In recent years, Dr. Toscano’s group has investigated neurovascular complications of Pompe in late-onset patients. “This was something that really surprised us because for several years we have investigated mainly heart, muscle, or respiratory manifestations of the disease, but the central nervous system was really neglected,” he said.

“Occasionally we did some brain MRIs and we found in even young patients some ischemic areas. We thought this was related to slowed circulation – that blood vessels in these patients are weak because they are impaired by glycogen accumulation.” Dr. Toscano and his colleagues followed that observation with a study of late-onset patients,⁴ in which they found that more than half had cerebrovascular abnormalities. “Even in, say, patients 30 to 35 years old we saw this – it’s unusual to have a vascular disorder at that age.”

Dr. Toscano and his colleagues also reported cerebral aneurysms⁵ in patients with Pompe disease and have recommended that clinicians conduct MRI or cerebral angiograms on patients as part of routine follow-up. Blood pressure in Pompe patients should be carefully watched and managed with antihypertensive medication as needed, he said.

Part of the problem is that the proteins in ERT are not able to cross the blood-brain barrier, Dr. Toscano noted, adding that researchers are investigating other treatments that can.
 

Pompe disease as a research model

The successful development of ERT for Pompe disease marked a boom in research interest into not just Pompe – for which several experimental therapies are currently in the pipeline – but for other myopathies and glycogen storage disorders.

“I think that Pompe has served as a template both as a muscle disease and a lysosomal storage disease, and so some of our learnings from Pompe have been applied across different diseases,” Dr. Kishnani said.

Studies in spinal muscular atrophy, for example, “in some ways mirrored what was done for Pompe – treatment trials were initiated in babies at the most severe end of the disease population with infantile disease, and used similar clinical trial endpoints,” Dr. Kishnani said. “Even for the later-onset end of the spectrum, the endpoints we used in Pompe for muscle strength and function have been relevant to many other neuromuscular disorders.”

Pompe disease research also ushered in a new appreciation of immune responses in protein replacement therapies, Dr. Kishnani noted.

“In the field today, you hear the term cross-reactive immunological material, or CRIM, all the time,” she said. “But when we first started talking about it in the space of Pompe disease, there was a lot of scientific debate about what the significance of CRIM-negative status was in relationship to the risk for development of high and sustained antibody titer and a poor clinical response. To understand this involved a lot of going back to the data and digging into the small subset of nonresponders. One of the powers of rare disease research is that every patient matters, and it’s important to understand what’s going on at the patient level rather than just the group data level.”
 

A robust pipeline

The decade and a half since the advent of ERT has seen what Dr. Toscano described as “an explosion of interest” in Pompe disease.

“We’re seeing an extraordinary number of papers on everything from clinical, biomarkers, genetics, and rehabilitation – this disease is now considered from every point of view, and this is very important for patients,” Dr. Toscano said. Alongside this has come industry interest in this rare disease, with several companies investigating a range of treatment approaches.

The existence of a treatment, “while not perfect,” he said, “has interested the patient associations and doctors to try and improve service to patients. Patients with Pompe disease are well attended, probably more so than patients with degenerative disorders in which there is no therapy.”

Last year the second ERT, avalglucosidase alfa (Nexviazyme, Sanofi Genzyme) was approved by the U.S. Food and Drug Administration to treat late-onset Pompe disease. The drug, currently being investigated in infants as well, was designed to improve the delivery of the therapeutic enzyme to muscles and enhance glycogen clearance, and results from ongoing trials suggest some functional and clinical benefit over standard ERT.

Other drugs in development for Pompe disease include substrate reduction therapies, which aim to reduce the storage of glycogen in cells, and therapies that improve residual function of mutant GAA enzyme in the body. These and other therapies in development have the potential to modify nervous system manifestations of Pompe disease.⁶

Because a single gene is implicated in Pompe disease, it has long been considered a good candidate for gene therapies that prompt the body to make stable enzyme. Seven companies are now investigating gene therapies in Pompe disease.⁷ Some of these deliver to skeletal muscles and others aim for the liver, where proteins are synthesized and secreted and adverse immune responses might be more easily mitigated. Other gene therapies use an ex vivo approach, removing and replacing cells in bone marrow.

Dr. Kishnani’s research group at Duke University is leading a small clinical trial in late-onset patients of a GAA gene transfer to the liver using adeno-associated virus (AAV) vectors.⁸

“We have started AAV gene therapy trials in in adults with Pompe disease and will later evaluate children because ERT is available as a standard of care, and so from a safety perspective this makes the most sense,” Dr. Kishnani said. “We do have challenges in the field of gene therapy, but I think if we are able to overcome the immune responses, and … to treat at a lower dose, there’s a very good pathway forward.”

Dr. Toscano and Dr. Kishnani have received reimbursement from Sanofi and other manufacturers for participation on advisory boards and as speakers.



Jennie Smith is a freelance journalist and editor specializing in medicine and health.

References

1. Musumeci O, Toscano A. Diagnostic tools in late onset Pompe disease (LOPD). Ann Transl Med. 2019 Jul;7(13):286. doi: 10.21037/atm.2019.06.60.

2. Filosto M et al. Assessing the role of anti rh-GAA in modulating response to ERT in a late-onset Pompe disease cohort from the Italian GSDII Study Group. Adv Ther. 2019 May;36(5):1177-1189. doi: 10.1007/s12325-019-00926-5.

3. Patel TT et al. The impact of antibodies in late-onset Pompe disease: A case series and literature review. Mol Genet Metab. 2012 Jul;106(3):301-9. doi: 10.1016/j.ymgme.2012.04.027.

4. Montagnese F et al. Intracranial arterial abnormalities in patients with late onset Pompe disease (LOPD). J Inherit Metab Dis. 2016 May;39(3):391-398. doi: 10.1007/s10545-015-9913-x.

5. Musumeci O et al. Central nervous system involvement in late-onset Pompe disease: Clues from neuroimaging and neuropsychological analysis. Eur J Neurol. 2019 Mar;26(3):442-e35. doi: 10.1111/ene.13835.

6. Edelmann MJ, Maegawa GHB. CNS-targeting therapies for lysosomal storage diseases: Current advances and challenges. Front Mol Biosci. 2020 Nov 12;7:559804. doi: 10.3389/fmolb.2020.559804

7. Ronzitti G et al. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):287. doi: 10.21037/atm.2019.04.67.

8. Kishnani PS, Koeberl DD. Liver depot gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):288. doi: 10.21037/atm.2019.05.02.

Until 2006, when a breakthrough therapy first made treatment possible, Pompe disease was a little-known metabolic myopathy fatal to infants. Those with later-onset disease experienced progressive, often severe disability into adulthood.

In this rare autosomal recessive disorder, which occurs in approximately one in 40,000 births worldwide, a deficiency or absence of the enzyme acid alpha-glucosidase causes glycogen to build up in the lysosomes of cells. While many tissues are affected, skeletal and cardiac muscle see the earliest involvement, with muscle hypotonia, cardiomyopathy, and breathing difficulties (mainly due to diaphragm weakness) comprising the hallmark symptoms of the infantile form. Muscle weakness and progressive respiratory failure are prominent in later-onset disease.

Diagnosis: Still room to improve

“Most neurologists will encounter a patient with Pompe disease,” said Dr. Kishnani, who has been working with Pompe for her entire career as a pediatrician and medical geneticist, treating patients of all ages and disease phenotypes.

“In newborns, diagnosis is more straightforward, because you’ve got an enlarged heart,” she said. And thanks to efforts of researchers like Dr. Kishnani and Pompe advocacy groups, Pompe disease is now a part of the RUSP (Recommended Uniform Screening Panel) for newborns; currently 28 U.S. states are screening for Pompe disease.

“The challenge really is for the later-onset cases, which are 80% of all cases,” Dr. Kishnani said.

Previously, muscle biopsies were the first step toward diagnosis. Dried blot spot assays to detect enzyme deficiency have since become the standard, along with other biochemical tests. Confirmation of the diagnosis is through gene sequencing panels to detect GAA mutations.

“Now that there is a treatment for Pompe disease and the availability of blood-based testing, many previously undiagnosed patients with limb girdle weakness are evaluated and the diagnostic odyssey ends,” Dr. Kishnani said. “But there is still a diagnostic delay, and many cases remain undiagnosed.”

Routine blood tests for creatine kinase and for liver enzymes can help point to Pompe disease. But elevated liver enzymes are often misinterpreted. “It’s about the ratios,” Dr. Kishnani said. “ALT is usually much more elevated if it is coming from a liver cause, and AST is usually higher than ALT if it is coming from muscle. But patients often end up getting a liver biopsy due to so-called elevated liver enzymes. As the workup continues, it is often later recognized that the source of the elevated enzymes is muscle involvement, and a referral to the geneticist or neurologist is made. Only then is appropriate testing to confirm a diagnosis initiated.”

Dr. Toscano, a neurologist who specializes in Pompe disease and other myopathies and who has published on tools for diagnosing late-onset Pompe disease,¹ said that clinicians should be vigilant when evaluating any patient with limb girdle weakness and elevated creatine kinase (CK) – “especially if the CK is under 2,000,” he said, “because it is very rare that patients with Pompe disease have a more elevated CK than that.”

“Elevated CK, myalgia, and exercise intolerance” should prompt clinicians to suspect Pompe disease in a patient of any age, Dr. Toscano said. “When you come across this, you should be very persistent and get to the end of the story.”

Dr. Toscano noted that the blood spot assay, while an important early step, is not fully diagnostic, “because you can have false positives.” The molecular GAA assay is used to confirm Pompe disease. But detecting pathogenic variants on the GAA gene – of which there are more than 500 – can be more complicated than it sounds. Whereas two mutations are required for Pompe disease, sometimes only one can be detected. Dr. Toscano said he also treated some patients for Pompe with only one known mutation but with unequivocal clinical and biochemical aspects of Pompe disease.

While delays in diagnosis for late-onset Pompe disease remain significant -- between 5 and 6 years on average for older patients, and up to 20 years for those with pediatric onset – both Dr. Kishnani and Dr. Toscano said they perceive them to be improving. With McArdle disease, another inherited glycogen storage disorder that is more common than Pompe disease but for which there is no treatment, “the delay is nearly 12 years,” Dr. Toscano said.
 

ERT: The sooner the better

Enzyme replacement therapy is indicated for all patients with Pompe disease. Currently two are commercially available: alglucosidase alfa (Lumizyme, Sanofi Genzyme), indicated for all forms of Pompe disease, and avalglucosidase alfa-ngpt (Nexviazyme, Sanofi Genzyme), approved in 2021 for later-onset Pompe, though its indications have yet to be fully defined.

The semimonthly infusions represent, to date, the only disease-modifying therapies commercially available. Enzyme replacement therapy can reverse cardiac damage seen in infants and allow them to meet developmental milestones previously unthinkable. In adults, it can slow progression, though many treated patients will still develop chronic disability and require a wheelchair, respiratory support, or both. “The phenotype of the patients we are seeing today is not as involved as it was prior to enzyme therapy,” said Dr. Kishnani, who was part of the research team that developed ERT and launched the first clinical trials. “This is across the disease spectrum.”

But optimal management means more than just getting a patient on therapy fast, Dr. Kishnani said.

“Very often the thinking is if the patient is on ERT, we’ve done right by the patient. Aspects we don’t look at enough include: Are we monitoring these patients well? Are patients being followed by a multidisciplinary team that includes cardiology, physical therapy, and pulmonary medicine? Are we doing appropriate musculoskeletal assessments? They might have sleep hypoventilation. The BiPap settings may not be correct. Or they have not been assessed for antibodies,” she said.

Many infants with severe phenotypes, notably those who produce no enzyme naturally, will develop immune reactions to the exogenous enzyme therapy. High antibody titers also have been seen and are associated with poor therapeutic response. While this is very clear in the infantile setting, late-onset patients also develop antibodies in response to ERT. In one study in 64 patients,² Dr. Toscano and his colleagues saw that antibodies may affect clinical response during the first 3 years of treatment, while a small study³ by Dr. Kishnani’s group saw clinical decline associated with high antibody titers in patients with late-onset disease.

While the relationship of specific titers to therapeutic response remains unclear, it is important to consider antibodies, along with other factors, in the monitoring of patients with Pompe disease. “We need to always ask, if a patient is falling behind, what could be the reason?” Dr. Kishnani said. “These are the things we as clinicians can do to improve or enhance the impact of ERT.”

Dr. Toscano noted that a common misconception about late-onset Pompe disease is that cardiac manifestations are minimal or absent, whereas as many as about 20% of patients will have heart problems and need to be carefully monitored.
 

Neurological manifestations

With patients surviving longer on ERT, researchers have been able to develop a deeper understanding of the natural history of Pompe disease. Increasingly, they are seeing it as a multisystem disease that includes central nervous system involvement.

“Is Pompe an overt neurodegenerative disease? I would say no,” Dr. Kishnani said. “But there is a neurological component that we’ve got to understand and follow more.”

Glycogen accumulation, she noted, has been found in anterior horn cells, motor neurons, and other parts of the brain. “We have been doing MRIs on children with infantile Pompe, and we have seen some white matter hyperintensities. The clinical significance of this finding is still emerging. Sometimes it is present, but the child is cognitively intact. We have had college graduates who have white matter hyperintensities. So putting it in context will be important. But we know that glycogen is ubiquitous, and autopsy studies have shown that it is present in the brain.”

In recent years, Dr. Toscano’s group has investigated neurovascular complications of Pompe in late-onset patients. “This was something that really surprised us because for several years we have investigated mainly heart, muscle, or respiratory manifestations of the disease, but the central nervous system was really neglected,” he said.

“Occasionally we did some brain MRIs and we found in even young patients some ischemic areas. We thought this was related to slowed circulation – that blood vessels in these patients are weak because they are impaired by glycogen accumulation.” Dr. Toscano and his colleagues followed that observation with a study of late-onset patients,⁴ in which they found that more than half had cerebrovascular abnormalities. “Even in, say, patients 30 to 35 years old we saw this – it’s unusual to have a vascular disorder at that age.”

Dr. Toscano and his colleagues also reported cerebral aneurysms⁵ in patients with Pompe disease and have recommended that clinicians conduct MRI or cerebral angiograms on patients as part of routine follow-up. Blood pressure in Pompe patients should be carefully watched and managed with antihypertensive medication as needed, he said.

Part of the problem is that the proteins in ERT are not able to cross the blood-brain barrier, Dr. Toscano noted, adding that researchers are investigating other treatments that can.
 

Pompe disease as a research model

The successful development of ERT for Pompe disease marked a boom in research interest into not just Pompe – for which several experimental therapies are currently in the pipeline – but for other myopathies and glycogen storage disorders.

“I think that Pompe has served as a template both as a muscle disease and a lysosomal storage disease, and so some of our learnings from Pompe have been applied across different diseases,” Dr. Kishnani said.

Studies in spinal muscular atrophy, for example, “in some ways mirrored what was done for Pompe – treatment trials were initiated in babies at the most severe end of the disease population with infantile disease, and used similar clinical trial endpoints,” Dr. Kishnani said. “Even for the later-onset end of the spectrum, the endpoints we used in Pompe for muscle strength and function have been relevant to many other neuromuscular disorders.”

Pompe disease research also ushered in a new appreciation of immune responses in protein replacement therapies, Dr. Kishnani noted.

“In the field today, you hear the term cross-reactive immunological material, or CRIM, all the time,” she said. “But when we first started talking about it in the space of Pompe disease, there was a lot of scientific debate about what the significance of CRIM-negative status was in relationship to the risk for development of high and sustained antibody titer and a poor clinical response. To understand this involved a lot of going back to the data and digging into the small subset of nonresponders. One of the powers of rare disease research is that every patient matters, and it’s important to understand what’s going on at the patient level rather than just the group data level.”
 

A robust pipeline

The decade and a half since the advent of ERT has seen what Dr. Toscano described as “an explosion of interest” in Pompe disease.

“We’re seeing an extraordinary number of papers on everything from clinical, biomarkers, genetics, and rehabilitation – this disease is now considered from every point of view, and this is very important for patients,” Dr. Toscano said. Alongside this has come industry interest in this rare disease, with several companies investigating a range of treatment approaches.

The existence of a treatment, “while not perfect,” he said, “has interested the patient associations and doctors to try and improve service to patients. Patients with Pompe disease are well attended, probably more so than patients with degenerative disorders in which there is no therapy.”

Last year the second ERT, avalglucosidase alfa (Nexviazyme, Sanofi Genzyme) was approved by the U.S. Food and Drug Administration to treat late-onset Pompe disease. The drug, currently being investigated in infants as well, was designed to improve the delivery of the therapeutic enzyme to muscles and enhance glycogen clearance, and results from ongoing trials suggest some functional and clinical benefit over standard ERT.

Other drugs in development for Pompe disease include substrate reduction therapies, which aim to reduce the storage of glycogen in cells, and therapies that improve residual function of mutant GAA enzyme in the body. These and other therapies in development have the potential to modify nervous system manifestations of Pompe disease.⁶

Because a single gene is implicated in Pompe disease, it has long been considered a good candidate for gene therapies that prompt the body to make stable enzyme. Seven companies are now investigating gene therapies in Pompe disease.⁷ Some of these deliver to skeletal muscles and others aim for the liver, where proteins are synthesized and secreted and adverse immune responses might be more easily mitigated. Other gene therapies use an ex vivo approach, removing and replacing cells in bone marrow.

Dr. Kishnani’s research group at Duke University is leading a small clinical trial in late-onset patients of a GAA gene transfer to the liver using adeno-associated virus (AAV) vectors.⁸

“We have started AAV gene therapy trials in in adults with Pompe disease and will later evaluate children because ERT is available as a standard of care, and so from a safety perspective this makes the most sense,” Dr. Kishnani said. “We do have challenges in the field of gene therapy, but I think if we are able to overcome the immune responses, and … to treat at a lower dose, there’s a very good pathway forward.”

Dr. Toscano and Dr. Kishnani have received reimbursement from Sanofi and other manufacturers for participation on advisory boards and as speakers.



Jennie Smith is a freelance journalist and editor specializing in medicine and health.

References

1. Musumeci O, Toscano A. Diagnostic tools in late onset Pompe disease (LOPD). Ann Transl Med. 2019 Jul;7(13):286. doi: 10.21037/atm.2019.06.60.

2. Filosto M et al. Assessing the role of anti rh-GAA in modulating response to ERT in a late-onset Pompe disease cohort from the Italian GSDII Study Group. Adv Ther. 2019 May;36(5):1177-1189. doi: 10.1007/s12325-019-00926-5.

3. Patel TT et al. The impact of antibodies in late-onset Pompe disease: A case series and literature review. Mol Genet Metab. 2012 Jul;106(3):301-9. doi: 10.1016/j.ymgme.2012.04.027.

4. Montagnese F et al. Intracranial arterial abnormalities in patients with late onset Pompe disease (LOPD). J Inherit Metab Dis. 2016 May;39(3):391-398. doi: 10.1007/s10545-015-9913-x.

5. Musumeci O et al. Central nervous system involvement in late-onset Pompe disease: Clues from neuroimaging and neuropsychological analysis. Eur J Neurol. 2019 Mar;26(3):442-e35. doi: 10.1111/ene.13835.

6. Edelmann MJ, Maegawa GHB. CNS-targeting therapies for lysosomal storage diseases: Current advances and challenges. Front Mol Biosci. 2020 Nov 12;7:559804. doi: 10.3389/fmolb.2020.559804

7. Ronzitti G et al. Progress and challenges of gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):287. doi: 10.21037/atm.2019.04.67.

8. Kishnani PS, Koeberl DD. Liver depot gene therapy for Pompe disease. Ann Transl Med. 2019 Jul;7(13):288. doi: 10.21037/atm.2019.05.02.

The number of cataloged rare diseases continues to grow every day. According to the National Human Genome Research Institute, more than 6,800 rare diseases have been identified and between 25 million and 30 million Americans are living with rare diseases today.

Thinking of rare diseases in categories

Many patients with undiagnosed rare diseases undergo what’s commonly referred to as a “diagnostic odyssey,” moving from one provider to another to try to find an explanation for a condition they may or may not know is rare. For some patients, this process can take many years or even decades. From the patient’s perspective, the main challenges are recognizing they have a problem that doesn’t fit a common disease model. Once they recognize they have a potential rare disease, working with a provider to find the right diagnosis among the “vast number of disease diagnoses and designations, and actually sifting through it to find the one that’s right for that patient” is the next challenge, said Dr. Summar.

However, knowledge of rare diseases among health care professionals is low, according to a 2019 paper published in the Orphanet Journal of Rare Diseases. In a survey from that paper asking general practitioners, pediatricians, specialists caring for adults, and specialists caring for children to evaluate their own knowledge of rare diseases, 42% of general practitioners said they had poor knowledge and 44% said they had a substandard understanding of rare diseases.

From a clinician’s standpoint, diagnosing rare diseases in their patients can be challenging, with the potential for overreferral or overdiagnosis. However, it is also easy to underdiagnose rare diseases by missing them, noted Dr. Summar. This issue can vary based on the experience of the provider, he said, because while general practitioners who recently began practicing may have had more exposure to rare diseases, for health care professionals who have been practicing for decades, “this is a new arrival in their field.”

During a busy day finding that extra time in an appointment to stop and question whether a patient might have a rare disease is another problem generalists face. “It is really tough for those general practitioners, because if you see 40 or 50 patients per day, how do you know which one of those [patients] were the ones that had something that wasn’t quite fitting or wasn’t quite ordinary?” he said.

When it comes to considering rare diseases in their patients, health care professionals in general practice should think in categories, rather than a particular rare disease, according to Dr. Summar. As the generalist is typically on the front lines of patient care, they don’t necessarily need to know everything about the rare disease they suspect a patient of having to help them. “You don’t need to know the specific gene and the specific mutation to make the diagnosis, or to even move the patient forward in the process,” he said.

The first steps a clinician can take include noticing when something with a patient is amiss, thinking about the disease category, and then creating a plan to move forward, such as referring the patient to a subspecialist. Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.

The framing of rare diseases as categories is a change in thinking over the last decade, said Dr. Summar. Whereas rare disease diagnoses previously focused on fitting certain criteria, the development of more refined genetic sequencing has allowed specialists to focus on categories and genes that affect rare diseases. “Getting at a diagnosis has really been turned up on its head, so that by employing both next-generation sequencing, newborn screening, and other [tools], we can actually get to diagnoses faster than we could before,” he said.

In terms of assessing for symptoms, health care professionals should be aware that “common” symptoms can be a sign of rare disease. What to look out for are the uncommon symptoms that create an “aha moment.” Having a “good filter” for sensing when something isn’t quite right with a patient is key. “It’s like any time when you’re screening things: You want high sensitivity, but you also have to have high specificity,” he said.

Another clinical pearl is that good communication between patient and provider is paramount. “We’re not always good listeners. Sometimes we hear what we expect to hear,” said Dr. Summar.
 

Rare disease warning signs

Within the context of rare neurological diseases, Dr. Summar noted one major category is delays in neurological development, which is typically identified in children or adolescents. As the most complex organ in the body, “the brain probably expresses more genes than any other tissue on a regular basis, both in its formation and its function,” said Dr. Summar. He said the single disease that rare disease specialists see most often is Down syndrome.

Another separate but overlapping major category is autism, identified in younger children through trouble with social interaction, lack of eye contact, and delays in speech and communication skills. A third major category is physical manifestations of neurological problems, such as in patients who have epilepsy.

A telltale sign in identifying a child with a potential rare neurological disease is when they are “not thriving in their development or not doing the things on track that you would expect, and you don’t have a really good answer for it,” said Dr. Summar. Generalists are normally on watch for developmental delays in newborns born premature or with a rough course in the nursery, but they should also be aware of delays in children born under otherwise typical circumstances. “If I have a patient who had normal pregnancy, normal labor and delivery, no real illnesses or anything like that, and yet wasn’t meeting those milestones, that’s a patient I would pay attention to,” he said.

Another clue general practitioners can use for suspecting rare diseases is when a patient is much sicker than usual during a routine illness like a cold or flu. “Those are patients we should be paying attention to because it may be there’s an underlying biochemical disorder or some disorder in how they’re responding to stress that’s just not quite right,” said Dr. Summar. How a patient responds to stressful situations can be a warning sign “because that can often unmask more severe symptoms in that rare disease and make it a little more apparent,” he said.
 

Learning more about rare diseases

Dr. Summar said he and his colleagues in the rare disease field have spent a lot of time working with medical schools to teach this mindset in their curricula. The concept is introduced in basic medical science courses and then reinforced in clinical rotations in the third or fourth year, he explained.

“One of the best places is during the pediatrics rotations in medical school,” he said. “Remember, kids are basically healthy. If a child has a chronic illness or a chronic disease, more often than not, it is probably a rare disease.”

For medical professionals not in pediatric practice, the concept is applied the same way for adult medicine. “You just want to make sure everyone takes a second when they have a patient and try not to assume. Don’t assume it’s exactly what it seems. Look at it carefully and make sure there’s not something else going on,” he said.

Health care professionals in general practice looking to learn more about rare diseases can increasingly find rare disease topics in their CME programs. Rare disease topics in CME programs are “one of the best places” to learn about the latest developments in the field, said Dr. Summar.
 

Will rare disease screening tools come to primary care?

Asking more doctors to refer out to rare disease specialists raises an issue: There simply aren’t enough rare disease specialists in the field to go around.

Dr. Summar said partnering testing – where a general practitioner contacts a specialist to begin the process of testing based on the suspected condition – is a good stopgap solution. Telemedicine, which rose in popularity during the COVID-19 pandemic, can also play an important role in connecting patients and their providers with rare disease specialists, especially for generalists in remote communities. Dr. Summar noted he continues to see approximately 30% of his patients this way today. Telemedicine appointments can take place in the patient’s home or at the provider’s office.

“It actually provides access to folks who otherwise might not be able to either take off from work for a day – particularly some of our single parent households – or have a child who just doesn’t travel well, or can’t really get there, even if it’s the patient themselves,” he explained. “We can see patients that historically would have had trouble or difficulty coming in, so for me, that’s been a good thing.”

Telemedicine also helps give access to care for more medically fragile patients, many of whom have rare diseases, he added. While some aspects of care need to occur in person, “it’s a good 80% or 90% solution for a lot of these things,” he said.

Sharing educational videos is another way for health care providers in general practice to inform patients and their families about rare diseases. Children’s National Medical Center has created a collection of these videos in a free app called GeneClips, which is available on major smartphone app stores. However, Dr. Summar emphasized that genetic counseling should still be performed by a rare disease specialist prior to testing.

“We’re still at the point where I think having genetic counseling for a family before they’re going into testing is really advisable, since a lot of the results have a probability assigned to them,” he said. “I don’t think we’re really at the level where a practitioner is going to, first of all, have the time to do those, and I don’t think there’s enough general public awareness of what these things mean.”

Although primary care providers may one day be able to perform more generalized sequencing in their own practice, that time has not yet come – but it is closer than you think. “The technology is there, and actually the cost has come down a lot,” said Dr. Summar.

One potential issue this would create is an additional discussion to manage expectations of test results with family when the results are unclear, which “actually takes more time than counseling about a yes or no, or even an outcome that is unexpected,” explained Dr. Summar.

“[W]e’re in a midlife period right now where we’re bringing forward this new technology, but we’ve got to continually prepare the field for it first,” he said. “I think in the future we’ll see that it has much greater utility in the general setting,” he said.


Jeff Craven is a freelance journalist specializing in medicine and health.

Suggested reading

Vandeborne L et al. Information needs of physicians regarding the diagnosis of rare diseases: A questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.

The number of cataloged rare diseases continues to grow every day. According to the National Human Genome Research Institute, more than 6,800 rare diseases have been identified and between 25 million and 30 million Americans are living with rare diseases today.

Thinking of rare diseases in categories

Many patients with undiagnosed rare diseases undergo what’s commonly referred to as a “diagnostic odyssey,” moving from one provider to another to try to find an explanation for a condition they may or may not know is rare. For some patients, this process can take many years or even decades. From the patient’s perspective, the main challenges are recognizing they have a problem that doesn’t fit a common disease model. Once they recognize they have a potential rare disease, working with a provider to find the right diagnosis among the “vast number of disease diagnoses and designations, and actually sifting through it to find the one that’s right for that patient” is the next challenge, said Dr. Summar.

However, knowledge of rare diseases among health care professionals is low, according to a 2019 paper published in the Orphanet Journal of Rare Diseases. In a survey from that paper asking general practitioners, pediatricians, specialists caring for adults, and specialists caring for children to evaluate their own knowledge of rare diseases, 42% of general practitioners said they had poor knowledge and 44% said they had a substandard understanding of rare diseases.

From a clinician’s standpoint, diagnosing rare diseases in their patients can be challenging, with the potential for overreferral or overdiagnosis. However, it is also easy to underdiagnose rare diseases by missing them, noted Dr. Summar. This issue can vary based on the experience of the provider, he said, because while general practitioners who recently began practicing may have had more exposure to rare diseases, for health care professionals who have been practicing for decades, “this is a new arrival in their field.”

During a busy day finding that extra time in an appointment to stop and question whether a patient might have a rare disease is another problem generalists face. “It is really tough for those general practitioners, because if you see 40 or 50 patients per day, how do you know which one of those [patients] were the ones that had something that wasn’t quite fitting or wasn’t quite ordinary?” he said.

When it comes to considering rare diseases in their patients, health care professionals in general practice should think in categories, rather than a particular rare disease, according to Dr. Summar. As the generalist is typically on the front lines of patient care, they don’t necessarily need to know everything about the rare disease they suspect a patient of having to help them. “You don’t need to know the specific gene and the specific mutation to make the diagnosis, or to even move the patient forward in the process,” he said.

The first steps a clinician can take include noticing when something with a patient is amiss, thinking about the disease category, and then creating a plan to move forward, such as referring the patient to a subspecialist. Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.

The framing of rare diseases as categories is a change in thinking over the last decade, said Dr. Summar. Whereas rare disease diagnoses previously focused on fitting certain criteria, the development of more refined genetic sequencing has allowed specialists to focus on categories and genes that affect rare diseases. “Getting at a diagnosis has really been turned up on its head, so that by employing both next-generation sequencing, newborn screening, and other [tools], we can actually get to diagnoses faster than we could before,” he said.

In terms of assessing for symptoms, health care professionals should be aware that “common” symptoms can be a sign of rare disease. What to look out for are the uncommon symptoms that create an “aha moment.” Having a “good filter” for sensing when something isn’t quite right with a patient is key. “It’s like any time when you’re screening things: You want high sensitivity, but you also have to have high specificity,” he said.

Another clinical pearl is that good communication between patient and provider is paramount. “We’re not always good listeners. Sometimes we hear what we expect to hear,” said Dr. Summar.
 

Rare disease warning signs

Within the context of rare neurological diseases, Dr. Summar noted one major category is delays in neurological development, which is typically identified in children or adolescents. As the most complex organ in the body, “the brain probably expresses more genes than any other tissue on a regular basis, both in its formation and its function,” said Dr. Summar. He said the single disease that rare disease specialists see most often is Down syndrome.

Another separate but overlapping major category is autism, identified in younger children through trouble with social interaction, lack of eye contact, and delays in speech and communication skills. A third major category is physical manifestations of neurological problems, such as in patients who have epilepsy.

A telltale sign in identifying a child with a potential rare neurological disease is when they are “not thriving in their development or not doing the things on track that you would expect, and you don’t have a really good answer for it,” said Dr. Summar. Generalists are normally on watch for developmental delays in newborns born premature or with a rough course in the nursery, but they should also be aware of delays in children born under otherwise typical circumstances. “If I have a patient who had normal pregnancy, normal labor and delivery, no real illnesses or anything like that, and yet wasn’t meeting those milestones, that’s a patient I would pay attention to,” he said.

Another clue general practitioners can use for suspecting rare diseases is when a patient is much sicker than usual during a routine illness like a cold or flu. “Those are patients we should be paying attention to because it may be there’s an underlying biochemical disorder or some disorder in how they’re responding to stress that’s just not quite right,” said Dr. Summar. How a patient responds to stressful situations can be a warning sign “because that can often unmask more severe symptoms in that rare disease and make it a little more apparent,” he said.
 

Learning more about rare diseases

Dr. Summar said he and his colleagues in the rare disease field have spent a lot of time working with medical schools to teach this mindset in their curricula. The concept is introduced in basic medical science courses and then reinforced in clinical rotations in the third or fourth year, he explained.

“One of the best places is during the pediatrics rotations in medical school,” he said. “Remember, kids are basically healthy. If a child has a chronic illness or a chronic disease, more often than not, it is probably a rare disease.”

For medical professionals not in pediatric practice, the concept is applied the same way for adult medicine. “You just want to make sure everyone takes a second when they have a patient and try not to assume. Don’t assume it’s exactly what it seems. Look at it carefully and make sure there’s not something else going on,” he said.

Health care professionals in general practice looking to learn more about rare diseases can increasingly find rare disease topics in their CME programs. Rare disease topics in CME programs are “one of the best places” to learn about the latest developments in the field, said Dr. Summar.
 

Will rare disease screening tools come to primary care?

Asking more doctors to refer out to rare disease specialists raises an issue: There simply aren’t enough rare disease specialists in the field to go around.

Dr. Summar said partnering testing – where a general practitioner contacts a specialist to begin the process of testing based on the suspected condition – is a good stopgap solution. Telemedicine, which rose in popularity during the COVID-19 pandemic, can also play an important role in connecting patients and their providers with rare disease specialists, especially for generalists in remote communities. Dr. Summar noted he continues to see approximately 30% of his patients this way today. Telemedicine appointments can take place in the patient’s home or at the provider’s office.

“It actually provides access to folks who otherwise might not be able to either take off from work for a day – particularly some of our single parent households – or have a child who just doesn’t travel well, or can’t really get there, even if it’s the patient themselves,” he explained. “We can see patients that historically would have had trouble or difficulty coming in, so for me, that’s been a good thing.”

Telemedicine also helps give access to care for more medically fragile patients, many of whom have rare diseases, he added. While some aspects of care need to occur in person, “it’s a good 80% or 90% solution for a lot of these things,” he said.

Sharing educational videos is another way for health care providers in general practice to inform patients and their families about rare diseases. Children’s National Medical Center has created a collection of these videos in a free app called GeneClips, which is available on major smartphone app stores. However, Dr. Summar emphasized that genetic counseling should still be performed by a rare disease specialist prior to testing.

“We’re still at the point where I think having genetic counseling for a family before they’re going into testing is really advisable, since a lot of the results have a probability assigned to them,” he said. “I don’t think we’re really at the level where a practitioner is going to, first of all, have the time to do those, and I don’t think there’s enough general public awareness of what these things mean.”

Although primary care providers may one day be able to perform more generalized sequencing in their own practice, that time has not yet come – but it is closer than you think. “The technology is there, and actually the cost has come down a lot,” said Dr. Summar.

One potential issue this would create is an additional discussion to manage expectations of test results with family when the results are unclear, which “actually takes more time than counseling about a yes or no, or even an outcome that is unexpected,” explained Dr. Summar.

“[W]e’re in a midlife period right now where we’re bringing forward this new technology, but we’ve got to continually prepare the field for it first,” he said. “I think in the future we’ll see that it has much greater utility in the general setting,” he said.


Jeff Craven is a freelance journalist specializing in medicine and health.

Suggested reading

Vandeborne L et al. Information needs of physicians regarding the diagnosis of rare diseases: A questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.

The number of cataloged rare diseases continues to grow every day. According to the National Human Genome Research Institute, more than 6,800 rare diseases have been identified and between 25 million and 30 million Americans are living with rare diseases today.

Thinking of rare diseases in categories

Many patients with undiagnosed rare diseases undergo what’s commonly referred to as a “diagnostic odyssey,” moving from one provider to another to try to find an explanation for a condition they may or may not know is rare. For some patients, this process can take many years or even decades. From the patient’s perspective, the main challenges are recognizing they have a problem that doesn’t fit a common disease model. Once they recognize they have a potential rare disease, working with a provider to find the right diagnosis among the “vast number of disease diagnoses and designations, and actually sifting through it to find the one that’s right for that patient” is the next challenge, said Dr. Summar.

However, knowledge of rare diseases among health care professionals is low, according to a 2019 paper published in the Orphanet Journal of Rare Diseases. In a survey from that paper asking general practitioners, pediatricians, specialists caring for adults, and specialists caring for children to evaluate their own knowledge of rare diseases, 42% of general practitioners said they had poor knowledge and 44% said they had a substandard understanding of rare diseases.

From a clinician’s standpoint, diagnosing rare diseases in their patients can be challenging, with the potential for overreferral or overdiagnosis. However, it is also easy to underdiagnose rare diseases by missing them, noted Dr. Summar. This issue can vary based on the experience of the provider, he said, because while general practitioners who recently began practicing may have had more exposure to rare diseases, for health care professionals who have been practicing for decades, “this is a new arrival in their field.”

During a busy day finding that extra time in an appointment to stop and question whether a patient might have a rare disease is another problem generalists face. “It is really tough for those general practitioners, because if you see 40 or 50 patients per day, how do you know which one of those [patients] were the ones that had something that wasn’t quite fitting or wasn’t quite ordinary?” he said.

When it comes to considering rare diseases in their patients, health care professionals in general practice should think in categories, rather than a particular rare disease, according to Dr. Summar. As the generalist is typically on the front lines of patient care, they don’t necessarily need to know everything about the rare disease they suspect a patient of having to help them. “You don’t need to know the specific gene and the specific mutation to make the diagnosis, or to even move the patient forward in the process,” he said.

The first steps a clinician can take include noticing when something with a patient is amiss, thinking about the disease category, and then creating a plan to move forward, such as referring the patient to a subspecialist. Learning to recognize when a cluster of symptoms doesn’t fit a pattern is important, as patients and their providers tend to gravitate toward diagnoses they are used to seeing, rather than suspecting a disease outside a usual pattern.

The framing of rare diseases as categories is a change in thinking over the last decade, said Dr. Summar. Whereas rare disease diagnoses previously focused on fitting certain criteria, the development of more refined genetic sequencing has allowed specialists to focus on categories and genes that affect rare diseases. “Getting at a diagnosis has really been turned up on its head, so that by employing both next-generation sequencing, newborn screening, and other [tools], we can actually get to diagnoses faster than we could before,” he said.

In terms of assessing for symptoms, health care professionals should be aware that “common” symptoms can be a sign of rare disease. What to look out for are the uncommon symptoms that create an “aha moment.” Having a “good filter” for sensing when something isn’t quite right with a patient is key. “It’s like any time when you’re screening things: You want high sensitivity, but you also have to have high specificity,” he said.

Another clinical pearl is that good communication between patient and provider is paramount. “We’re not always good listeners. Sometimes we hear what we expect to hear,” said Dr. Summar.
 

Rare disease warning signs

Within the context of rare neurological diseases, Dr. Summar noted one major category is delays in neurological development, which is typically identified in children or adolescents. As the most complex organ in the body, “the brain probably expresses more genes than any other tissue on a regular basis, both in its formation and its function,” said Dr. Summar. He said the single disease that rare disease specialists see most often is Down syndrome.

Another separate but overlapping major category is autism, identified in younger children through trouble with social interaction, lack of eye contact, and delays in speech and communication skills. A third major category is physical manifestations of neurological problems, such as in patients who have epilepsy.

A telltale sign in identifying a child with a potential rare neurological disease is when they are “not thriving in their development or not doing the things on track that you would expect, and you don’t have a really good answer for it,” said Dr. Summar. Generalists are normally on watch for developmental delays in newborns born premature or with a rough course in the nursery, but they should also be aware of delays in children born under otherwise typical circumstances. “If I have a patient who had normal pregnancy, normal labor and delivery, no real illnesses or anything like that, and yet wasn’t meeting those milestones, that’s a patient I would pay attention to,” he said.

Another clue general practitioners can use for suspecting rare diseases is when a patient is much sicker than usual during a routine illness like a cold or flu. “Those are patients we should be paying attention to because it may be there’s an underlying biochemical disorder or some disorder in how they’re responding to stress that’s just not quite right,” said Dr. Summar. How a patient responds to stressful situations can be a warning sign “because that can often unmask more severe symptoms in that rare disease and make it a little more apparent,” he said.
 

Learning more about rare diseases

Dr. Summar said he and his colleagues in the rare disease field have spent a lot of time working with medical schools to teach this mindset in their curricula. The concept is introduced in basic medical science courses and then reinforced in clinical rotations in the third or fourth year, he explained.

“One of the best places is during the pediatrics rotations in medical school,” he said. “Remember, kids are basically healthy. If a child has a chronic illness or a chronic disease, more often than not, it is probably a rare disease.”

For medical professionals not in pediatric practice, the concept is applied the same way for adult medicine. “You just want to make sure everyone takes a second when they have a patient and try not to assume. Don’t assume it’s exactly what it seems. Look at it carefully and make sure there’s not something else going on,” he said.

Health care professionals in general practice looking to learn more about rare diseases can increasingly find rare disease topics in their CME programs. Rare disease topics in CME programs are “one of the best places” to learn about the latest developments in the field, said Dr. Summar.
 

Will rare disease screening tools come to primary care?

Asking more doctors to refer out to rare disease specialists raises an issue: There simply aren’t enough rare disease specialists in the field to go around.

Dr. Summar said partnering testing – where a general practitioner contacts a specialist to begin the process of testing based on the suspected condition – is a good stopgap solution. Telemedicine, which rose in popularity during the COVID-19 pandemic, can also play an important role in connecting patients and their providers with rare disease specialists, especially for generalists in remote communities. Dr. Summar noted he continues to see approximately 30% of his patients this way today. Telemedicine appointments can take place in the patient’s home or at the provider’s office.

“It actually provides access to folks who otherwise might not be able to either take off from work for a day – particularly some of our single parent households – or have a child who just doesn’t travel well, or can’t really get there, even if it’s the patient themselves,” he explained. “We can see patients that historically would have had trouble or difficulty coming in, so for me, that’s been a good thing.”

Telemedicine also helps give access to care for more medically fragile patients, many of whom have rare diseases, he added. While some aspects of care need to occur in person, “it’s a good 80% or 90% solution for a lot of these things,” he said.

Sharing educational videos is another way for health care providers in general practice to inform patients and their families about rare diseases. Children’s National Medical Center has created a collection of these videos in a free app called GeneClips, which is available on major smartphone app stores. However, Dr. Summar emphasized that genetic counseling should still be performed by a rare disease specialist prior to testing.

“We’re still at the point where I think having genetic counseling for a family before they’re going into testing is really advisable, since a lot of the results have a probability assigned to them,” he said. “I don’t think we’re really at the level where a practitioner is going to, first of all, have the time to do those, and I don’t think there’s enough general public awareness of what these things mean.”

Although primary care providers may one day be able to perform more generalized sequencing in their own practice, that time has not yet come – but it is closer than you think. “The technology is there, and actually the cost has come down a lot,” said Dr. Summar.

One potential issue this would create is an additional discussion to manage expectations of test results with family when the results are unclear, which “actually takes more time than counseling about a yes or no, or even an outcome that is unexpected,” explained Dr. Summar.

“[W]e’re in a midlife period right now where we’re bringing forward this new technology, but we’ve got to continually prepare the field for it first,” he said. “I think in the future we’ll see that it has much greater utility in the general setting,” he said.


Jeff Craven is a freelance journalist specializing in medicine and health.

Suggested reading

Vandeborne L et al. Information needs of physicians regarding the diagnosis of rare diseases: A questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.

The National Organization for Rare Disorders (NORD)is tremendously grateful to the dedicated healthcare professionals who, despite long days and heavy workloads, continue to seek the latest information on medical advances that might be helpful to their patients. Please know that your commitment and support are tremendously important to the patients and families whom we serve.

As you may be aware, NORD is a nonprofit organization that was established in 1983 to provide advocacy, education, patient/family services and research on behalf of all Americans affected by rare diseases and the medical professionals providing their care.

Gregory Twachtman/MDedge News

As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.

Today, we are living in one of the most exciting periods in medical history, with innovative new diagnostics and treatments being developed or on the horizon. You’ll find information about these medical advances, as well as resources for yourself and your patients, on the NORD website including our Rare Disease Database, Video Library, CME programs and resources, and newsletter for medical professionals.

You’ll also find information about the annual NORD Rare Diseases and Orphan Products Breakthrough Summit, the largest annual conference for professionals and patients in the rare community, along with our annual conference specifically for patients and families, the “Living Rare, Living Stronger Family Forum.”

This issue of the Rare Neurological Diseases Special Report features articles from rare disease medical experts on specific diseases, including spinal muscular atrophy, Pompe disease, and Rett syndrome, as well as more general topics such as genetic therapies for neuromuscular diseases.

Also in this issue are articles on new and exciting initiatives such as the “NORD Rare Disease Centers of Excellence.” These 31 centers, geographically dispersed across the nation, represent an attempt to provide a strong, national network of support for both patients and medical professionals to promote earlier diagnosis and optimal care, regardless of location.

An interview in this issue with one of NORD’s longtime medical advisors and a leading rare disease expert provides advice for community physicians and other HCPs related to diagnosing rare diseases and approaches that may help shorten the diagnostic odyssey for patients. In addition, you can read about how patient advocacy organizations are collecting and managing a precious asset – patient data – to advance understanding of diseases, even extremely rare ones, and support research.

We are grateful for the work you do and for your commitment to your patients, including those with extremely rare or newly identified diseases. We invite you to visit the NORD website often, sign up for our newsletter for medical professionals and contact NORD at any time if we can be helpful to you.

Peter L. Saltonstall, president and CEO 
National Organization for Rare Disorders (NORD)

The National Organization for Rare Disorders (NORD)is tremendously grateful to the dedicated healthcare professionals who, despite long days and heavy workloads, continue to seek the latest information on medical advances that might be helpful to their patients. Please know that your commitment and support are tremendously important to the patients and families whom we serve.

As you may be aware, NORD is a nonprofit organization that was established in 1983 to provide advocacy, education, patient/family services and research on behalf of all Americans affected by rare diseases and the medical professionals providing their care.

Gregory Twachtman/MDedge News

As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.

Today, we are living in one of the most exciting periods in medical history, with innovative new diagnostics and treatments being developed or on the horizon. You’ll find information about these medical advances, as well as resources for yourself and your patients, on the NORD website including our Rare Disease Database, Video Library, CME programs and resources, and newsletter for medical professionals.

You’ll also find information about the annual NORD Rare Diseases and Orphan Products Breakthrough Summit, the largest annual conference for professionals and patients in the rare community, along with our annual conference specifically for patients and families, the “Living Rare, Living Stronger Family Forum.”

This issue of the Rare Neurological Diseases Special Report features articles from rare disease medical experts on specific diseases, including spinal muscular atrophy, Pompe disease, and Rett syndrome, as well as more general topics such as genetic therapies for neuromuscular diseases.

Also in this issue are articles on new and exciting initiatives such as the “NORD Rare Disease Centers of Excellence.” These 31 centers, geographically dispersed across the nation, represent an attempt to provide a strong, national network of support for both patients and medical professionals to promote earlier diagnosis and optimal care, regardless of location.

An interview in this issue with one of NORD’s longtime medical advisors and a leading rare disease expert provides advice for community physicians and other HCPs related to diagnosing rare diseases and approaches that may help shorten the diagnostic odyssey for patients. In addition, you can read about how patient advocacy organizations are collecting and managing a precious asset – patient data – to advance understanding of diseases, even extremely rare ones, and support research.

We are grateful for the work you do and for your commitment to your patients, including those with extremely rare or newly identified diseases. We invite you to visit the NORD website often, sign up for our newsletter for medical professionals and contact NORD at any time if we can be helpful to you.

Peter L. Saltonstall, president and CEO 
National Organization for Rare Disorders (NORD)

The National Organization for Rare Disorders (NORD)is tremendously grateful to the dedicated healthcare professionals who, despite long days and heavy workloads, continue to seek the latest information on medical advances that might be helpful to their patients. Please know that your commitment and support are tremendously important to the patients and families whom we serve.

As you may be aware, NORD is a nonprofit organization that was established in 1983 to provide advocacy, education, patient/family services and research on behalf of all Americans affected by rare diseases and the medical professionals providing their care.

Gregory Twachtman/MDedge News

As we approach NORD’s 40th anniversary, it is astonishing to realize how far we all have come since the early 1980s, when rare disease patients and their medical providers were essentially on their own to navigate the challenging waters of rare disease diagnosis and treatment.

Today, we are living in one of the most exciting periods in medical history, with innovative new diagnostics and treatments being developed or on the horizon. You’ll find information about these medical advances, as well as resources for yourself and your patients, on the NORD website including our Rare Disease Database, Video Library, CME programs and resources, and newsletter for medical professionals.

You’ll also find information about the annual NORD Rare Diseases and Orphan Products Breakthrough Summit, the largest annual conference for professionals and patients in the rare community, along with our annual conference specifically for patients and families, the “Living Rare, Living Stronger Family Forum.”

This issue of the Rare Neurological Diseases Special Report features articles from rare disease medical experts on specific diseases, including spinal muscular atrophy, Pompe disease, and Rett syndrome, as well as more general topics such as genetic therapies for neuromuscular diseases.

Also in this issue are articles on new and exciting initiatives such as the “NORD Rare Disease Centers of Excellence.” These 31 centers, geographically dispersed across the nation, represent an attempt to provide a strong, national network of support for both patients and medical professionals to promote earlier diagnosis and optimal care, regardless of location.

An interview in this issue with one of NORD’s longtime medical advisors and a leading rare disease expert provides advice for community physicians and other HCPs related to diagnosing rare diseases and approaches that may help shorten the diagnostic odyssey for patients. In addition, you can read about how patient advocacy organizations are collecting and managing a precious asset – patient data – to advance understanding of diseases, even extremely rare ones, and support research.

We are grateful for the work you do and for your commitment to your patients, including those with extremely rare or newly identified diseases. We invite you to visit the NORD website often, sign up for our newsletter for medical professionals and contact NORD at any time if we can be helpful to you.

Peter L. Saltonstall, president and CEO 
National Organization for Rare Disorders (NORD)

Thankfully, the COVID pandemic has not killed the spirit of innovation and the relentless search for answers in the rare disease community. There were several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing. This 7th annual issue of the Rare Neurological Disease Special Report highlights some of these developments.

For those of you who have been following the Rare Neurological Disease Special Report over the years, it is with great pride that I report that last year’s issue won a prestigious B2B award. The 2021 issue, our 6th annual issue, won an American Society of Business Publication Editors (ASBPE) Silver Regional Award for excellence in an annual publication. It has been our honor over the years to partner with the National Organization for Rare Disorders (NORD) to serve the rare neurological disease community. That effort is rewarding enough. Winning an award is icing on the cake but much appreciated.

—Glenn Williams, VP, Group Editor; Neurology Reviews and MDedge Neurology

Thankfully, the COVID pandemic has not killed the spirit of innovation and the relentless search for answers in the rare disease community. There were several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing. This 7th annual issue of the Rare Neurological Disease Special Report highlights some of these developments.

For those of you who have been following the Rare Neurological Disease Special Report over the years, it is with great pride that I report that last year’s issue won a prestigious B2B award. The 2021 issue, our 6th annual issue, won an American Society of Business Publication Editors (ASBPE) Silver Regional Award for excellence in an annual publication. It has been our honor over the years to partner with the National Organization for Rare Disorders (NORD) to serve the rare neurological disease community. That effort is rewarding enough. Winning an award is icing on the cake but much appreciated.

—Glenn Williams, VP, Group Editor; Neurology Reviews and MDedge Neurology

Thankfully, the COVID pandemic has not killed the spirit of innovation and the relentless search for answers in the rare disease community. There were several notable FDA approvals in 2021 and early 2022, emerging genetic therapies for monogenetic disorders, and recent advances in rare disease diagnosis and testing. This 7th annual issue of the Rare Neurological Disease Special Report highlights some of these developments.

For those of you who have been following the Rare Neurological Disease Special Report over the years, it is with great pride that I report that last year’s issue won a prestigious B2B award. The 2021 issue, our 6th annual issue, won an American Society of Business Publication Editors (ASBPE) Silver Regional Award for excellence in an annual publication. It has been our honor over the years to partner with the National Organization for Rare Disorders (NORD) to serve the rare neurological disease community. That effort is rewarding enough. Winning an award is icing on the cake but much appreciated.

—Glenn Williams, VP, Group Editor; Neurology Reviews and MDedge Neurology

The term myasthenia gravis (MG), from the Latin “grave muscle weakness,” denotes the rare autoimmune disorder characterized by dysfunction at the neuromuscular junction.¹ The clinical presentation of the disease is variable but most often includes ocular symptoms, such as ptosis and diplopia, bulbar weakness, and muscle fatigue upon exertion.^2,3 Severe symptoms can lead to myasthenic crisis, in which generalized weakness can affect respiratory muscles, leading to possible intubation or death.^2,3

Onset of disease ranges from childhood to late adulthood, and largely depends on the subgroup of disease and the age of the patient.⁴ Although complications from MG can arise, treatment methods have considerably reduced the risk of MG-associated mortality, with the current rate estimated to be 0.06 to 0.89 deaths for every 1 million person-years (that is, approximately 5% of cases).^3,5
 

Pathophysiology

MG is caused by binding of autoimmune antibodies to postsynaptic receptors and by molecules that prevent signal transduction at the muscle endplate.^2,4,6,7 The main culprit behind the pathology (in approximately 85% of cases) is an autoimmune antibody for the acetylcholine receptor (AChR); however, other offending antibodies – against muscle-specific serine kinases (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the proteoglycan agrin – are known, although at a lower frequency (in approximately 15% of cases).^4,8 These antibodies prevent signal transmission by blocking, destroying, or disrupting the clustering of AChR at the muscle endplate, a necessary step in formation of the neuromuscular junction.^4,8,9

• AChR antibody-positive.
• MuSK antibody-positive.
• LRP4 antibody-positive.
• Seronegative MG.

Classifying MG into subgroups gives insight into the functional expectations and potential treatment options for a given patient, although expectations can vary.²

Regrettably, the well-understood pathophysiology, diagnosis, and prognosis of MG have limited investigation and development of new therapies. Additionally, mainstay treatments, such as thymectomy and prednisone, work to alleviate symptoms for most patients, and have also contributed to periods of slowed research and development. However, treatment of refractory MG has, in recent years, become the subject of research on new therapeutic options, aimed at treating heterogeneous disease populations.¹⁰

In this review, we discuss the diagnosis of, and treatment options for, MG, and provide an update on promising options in the therapeutic pipeline.

Diagnosis

Distinguishing MG from other neuromuscular junction disorders is a pertinent step before treatment. Although the biomarkers discussed in this section are sensitive for making a diagnosis of MG, additional research is needed to classify seronegative patients who do not have circulating autoantibodies that are pathognomonic for MG.¹¹

Consensus on treatment standards

A quantitative assessment of best options for treating MG was conducted by leading experts,¹³ who reached consensus that primary outcomes in treating MG are reached when a patient presents without symptoms or limitations on daily activities; or has only slight weakness or fatigue in some muscles.¹³

Emerging therapies

Although conventional treatments for MG are well-established, 10% to 20% of MG patients remain refractory to therapeutic intervention.²¹ These patients are more susceptible to myasthenic crisis, which can result in hospitalization, intubation, and death.²¹ As mentioned, rescue therapies, including plasmapheresis and IVIg, are imperative to achieve remission of refractory MG, but such remission is unsustainable. Risks associated with these therapies, including contraindications and patient comorbidity, and their limited availability have prevented plasmapheresis and IVIg from being reliable interventions.¹²

These shortcomings, along with promising results from randomized clinical trials of newer modes of pharmacotherapeutic intervention, have increased interest in new therapies for MG. For example, complement pathway and neonatal Fc receptor (FcRn) inhibitors have recently shown promise in removing pathogenic autoimmune antibodies.¹⁸

Efgartigimod. FcRn is of interest in treating generalized MG because of its capacity to recycle and extend the half-life of IgG.²² Efgartigimod is a high-affinity FcRn inhibitor that simultaneously reduces IgG recycling and increases its degradation.²² This therapy is unique: it is highly selective for IgG, whereas other FcRn therapies are nonspecific, causing an undesirable decrease in other immunoglobulin and albumin levels.²² In December 2021, the Food and Drug Administration approved efgartigimod for the treatment of AChR-positive generalized MG.²³

Zilucoplan is a subcutaneously administered complement inhibitor that has completed phase 3 clinical trials.^18,24 The drug works by inhibiting cleavage of proteins C5a and C5b in the terminal complement complex, a necessary step in forming cytotoxic pores on targeted cells.^18,24 Zilucoplan also prevents tissue damage and destruction of signal transmission at the postsynaptic membrane.²⁵ Clinical trials have already established improvement in the Quantitative MG Score and the Myasthenia Gravis Activities of Daily Living Score in patients with generalized MG.^18,24

Zilucoplan is similar to eculizumab, but targets a different binding site, allowing for treatment of heterogeneous MG populations who have a mutation in the eculizumab target antigen.²⁶ Additionally, due to specific drug-body interactions, parameters for treatment using zilucoplan are broader than for therapies such as eculizumab. In a Zilucoplan press-release, the complement inhibitor showed statistically significant improvement in the treatment group of generalized, AChR-positive MG patients compared to the placebo group. Tolerability and safety was also a favorable finding in this study. However, a similar rate of treatment-emergent adverse events were recorded between the treatment group (76.7%) and placebo group (70.5%) which could indicate that the clinical application of this treatment is still forthcoming.²⁷ If zilucoplan is approved by the FDA, it will be used earlier in disease progression and for a larger subset of patients.²⁶

Nipocalimab is another immunoglobulin G1, FcRn antibody that reduces IgG levels in blood.^27,28 A phase 2 clinical study in patients with AChR-positive or MuSK antibody–associated MG showed that 52% of patients who received nipocalimab had a significant reduction in the Myasthenia Gravis Activities of Daily Living Score 4 weeks after infusion.²⁸ Phase 3 studies for adults with generalized MG are underway and are expected to conclude in April 2026.²⁹
 

Looking forward

Despite emerging therapies aimed at treating IgG in both refractory and nonrefractory MG, there is still a need for research into biomarkers that further differentiate disease. Developing research into new biomarkers, such as circulating microRNAs, gives insight into the promise of personalized medicine, which can shape the landscape of MG and other disorders.³⁰ As of August 2022, only two clinical trials are slated for investigation into new biomarkers for MG.

Although the treatment of MG might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies in coming years.
 

Mr. van der Eb is a second-year candidate in the master’s of science in applied life sciences program, Keck Graduate Institute, Claremont, Calif.; he has an associate’s degree in natural sciences from Pasadena City College, Calif., and a bachelor’s degree in biological sciences from the University of California, Irvine. Ms. Toruno is a graduate from the master’s of science in applied life sciences program, Keck Graduate Institute; she has a bachelor’s degree in psychology, with a minor in biological sciences, from the University of California, Irvine. Dr. Laird is director of clinical education and professor of practice for the master’s of science in physician assistant studies program, Keck Graduate Institute; he practices clinically in general and thoracic surgery.

The authors report no conflict of interest related to this article.

References

1. Gilhus NE et al. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y.

2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.

3. Dresser L et al. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021 May;10(11):2235. doi: 10.3390/jcm10112235.

4. Iyer SR et al. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021 Jul;22(15):8058. doi: 10.3390/ijms22158058.

5. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: Classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018 May;36(2):253-60. doi: 10.1016/j.ncl.2018.01.002.

6. Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021 Dec;21(12):798-813. doi: 10.1038/s41577-021-00543-w.

7. Drachman DB et al. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116-22. doi: 10.1056/NEJM197805182982004.

8. Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108. doi: 10.1159/000212371.

9. Zhang HL, Peng HB. Mechanism of acetylcholine receptor cluster formation induced by DC electric field. PLoS One. 2011;6(10):e26805. doi: 10.1371/journal.pone.0026805.

10. Fichtner ML et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776.

11. Tzartos JS et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-87. doi: 10.1002/acn3.26.

12. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-22. doi: 10.1212/WNL.0000000000011124.

13. Cortés-Vicente E et al. Myasthenia gravis treatment updates. Curr Treat Options Neurol. 2020 Jul 15;22(8):24. doi: 10.1007/s11940-020-00632-6.

14. Tannemaat MR, Verschuuren JJGM. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020 Feb;30(2):111-9. doi: 10.1016/j.nmd.2019.12.003.

15. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014 Jun;15(4):167-78. doi: 10.1097/CND.0000000000000034.

16. Sanders DB et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25. doi: 10.1212/WNL.0000000000002790.

17. Evoli A, Meacci E. An update on thymectomy in myasthenia gravis. Expert Rev Neurother. 2019 Sep;19(9):823-33. doi: 10.1080/14737175.2019.1600404.

18. Habib AA et al. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020 Nov;62(5):579-92. doi: 10.1002/mus.26919.

19. O’Sullivan KE et al. A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy. Ann Cardiothorac Surg. 2019 Mar;8(2):174-93. doi: 10.21037/acs.2019.02.04.

20. Wolfe GI et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-22. doi: 10.1056/NEJMoa1602489.

21. Schneider-Gold C et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019 Mar 1;12:1756286419832242. doi: 10.1177/1756286419832242.

22. Howard JF Jr et al; ADAPT Investigator Study Group. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-36. doi: 10.1016/S1474-4422(21)00159-9.

23. U.S. Food and Drug Administration. FDA approves new treatment for myasthenia gravis. News release. Dec 17, 2021. Accessed Feb 21, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis.

24. Ra Pharmaceuticals. A phase 3, multicenter, randomized, double blind, placebo-controlled study to confirm the safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04115293. Updated Jan 28, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04115293.

25. Howard JF Jr et al. Zilucoplan: An investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody–positive generalized myasthenia gravis. Expert Opin Investig Drugs. 2021 May;30(5):483-93. doi: 10.1080/13543784.2021.1897567.

26. Albazli K et al. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917.

27. UCB announces positive Phase 3 results for rozanolixizumab in generalized myasthenia gravis. UCB press release. December 10. 2021. Accessed August 15, 2022. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-positive-Phase-3-results-for-rozanolixizumab-in-generalized-myasthenia-gravis.

28. Keller CW et al. Fc-receptor targeted therapies for the treatment of myasthenia gravis. Int J Mol Sci. 2021 May;22(11):5755. doi: 10.3390/ijms22115755.

29. Janssen Research & Development LLC. Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04951622. Updated Feb 17, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04951622.

30. Sabre L et al. Circulating miRNAs as potential biomarkers in myasthenia gravis: Tools for personalized medicine. Front Immunol. 2020 Mar 4;11:213. doi: 10.3389/fimmu.2020.00213.


 

The term myasthenia gravis (MG), from the Latin “grave muscle weakness,” denotes the rare autoimmune disorder characterized by dysfunction at the neuromuscular junction.¹ The clinical presentation of the disease is variable but most often includes ocular symptoms, such as ptosis and diplopia, bulbar weakness, and muscle fatigue upon exertion.^2,3 Severe symptoms can lead to myasthenic crisis, in which generalized weakness can affect respiratory muscles, leading to possible intubation or death.^2,3

Onset of disease ranges from childhood to late adulthood, and largely depends on the subgroup of disease and the age of the patient.⁴ Although complications from MG can arise, treatment methods have considerably reduced the risk of MG-associated mortality, with the current rate estimated to be 0.06 to 0.89 deaths for every 1 million person-years (that is, approximately 5% of cases).^3,5
 

Pathophysiology

MG is caused by binding of autoimmune antibodies to postsynaptic receptors and by molecules that prevent signal transduction at the muscle endplate.^2,4,6,7 The main culprit behind the pathology (in approximately 85% of cases) is an autoimmune antibody for the acetylcholine receptor (AChR); however, other offending antibodies – against muscle-specific serine kinases (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the proteoglycan agrin – are known, although at a lower frequency (in approximately 15% of cases).^4,8 These antibodies prevent signal transmission by blocking, destroying, or disrupting the clustering of AChR at the muscle endplate, a necessary step in formation of the neuromuscular junction.^4,8,9

• AChR antibody-positive.
• MuSK antibody-positive.
• LRP4 antibody-positive.
• Seronegative MG.

Classifying MG into subgroups gives insight into the functional expectations and potential treatment options for a given patient, although expectations can vary.²

Regrettably, the well-understood pathophysiology, diagnosis, and prognosis of MG have limited investigation and development of new therapies. Additionally, mainstay treatments, such as thymectomy and prednisone, work to alleviate symptoms for most patients, and have also contributed to periods of slowed research and development. However, treatment of refractory MG has, in recent years, become the subject of research on new therapeutic options, aimed at treating heterogeneous disease populations.¹⁰

In this review, we discuss the diagnosis of, and treatment options for, MG, and provide an update on promising options in the therapeutic pipeline.

Diagnosis

Distinguishing MG from other neuromuscular junction disorders is a pertinent step before treatment. Although the biomarkers discussed in this section are sensitive for making a diagnosis of MG, additional research is needed to classify seronegative patients who do not have circulating autoantibodies that are pathognomonic for MG.¹¹

Consensus on treatment standards

A quantitative assessment of best options for treating MG was conducted by leading experts,¹³ who reached consensus that primary outcomes in treating MG are reached when a patient presents without symptoms or limitations on daily activities; or has only slight weakness or fatigue in some muscles.¹³

Emerging therapies

Although conventional treatments for MG are well-established, 10% to 20% of MG patients remain refractory to therapeutic intervention.²¹ These patients are more susceptible to myasthenic crisis, which can result in hospitalization, intubation, and death.²¹ As mentioned, rescue therapies, including plasmapheresis and IVIg, are imperative to achieve remission of refractory MG, but such remission is unsustainable. Risks associated with these therapies, including contraindications and patient comorbidity, and their limited availability have prevented plasmapheresis and IVIg from being reliable interventions.¹²

These shortcomings, along with promising results from randomized clinical trials of newer modes of pharmacotherapeutic intervention, have increased interest in new therapies for MG. For example, complement pathway and neonatal Fc receptor (FcRn) inhibitors have recently shown promise in removing pathogenic autoimmune antibodies.¹⁸

Efgartigimod. FcRn is of interest in treating generalized MG because of its capacity to recycle and extend the half-life of IgG.²² Efgartigimod is a high-affinity FcRn inhibitor that simultaneously reduces IgG recycling and increases its degradation.²² This therapy is unique: it is highly selective for IgG, whereas other FcRn therapies are nonspecific, causing an undesirable decrease in other immunoglobulin and albumin levels.²² In December 2021, the Food and Drug Administration approved efgartigimod for the treatment of AChR-positive generalized MG.²³

Zilucoplan is a subcutaneously administered complement inhibitor that has completed phase 3 clinical trials.^18,24 The drug works by inhibiting cleavage of proteins C5a and C5b in the terminal complement complex, a necessary step in forming cytotoxic pores on targeted cells.^18,24 Zilucoplan also prevents tissue damage and destruction of signal transmission at the postsynaptic membrane.²⁵ Clinical trials have already established improvement in the Quantitative MG Score and the Myasthenia Gravis Activities of Daily Living Score in patients with generalized MG.^18,24

Zilucoplan is similar to eculizumab, but targets a different binding site, allowing for treatment of heterogeneous MG populations who have a mutation in the eculizumab target antigen.²⁶ Additionally, due to specific drug-body interactions, parameters for treatment using zilucoplan are broader than for therapies such as eculizumab. In a Zilucoplan press-release, the complement inhibitor showed statistically significant improvement in the treatment group of generalized, AChR-positive MG patients compared to the placebo group. Tolerability and safety was also a favorable finding in this study. However, a similar rate of treatment-emergent adverse events were recorded between the treatment group (76.7%) and placebo group (70.5%) which could indicate that the clinical application of this treatment is still forthcoming.²⁷ If zilucoplan is approved by the FDA, it will be used earlier in disease progression and for a larger subset of patients.²⁶

Nipocalimab is another immunoglobulin G1, FcRn antibody that reduces IgG levels in blood.^27,28 A phase 2 clinical study in patients with AChR-positive or MuSK antibody–associated MG showed that 52% of patients who received nipocalimab had a significant reduction in the Myasthenia Gravis Activities of Daily Living Score 4 weeks after infusion.²⁸ Phase 3 studies for adults with generalized MG are underway and are expected to conclude in April 2026.²⁹
 

Looking forward

Despite emerging therapies aimed at treating IgG in both refractory and nonrefractory MG, there is still a need for research into biomarkers that further differentiate disease. Developing research into new biomarkers, such as circulating microRNAs, gives insight into the promise of personalized medicine, which can shape the landscape of MG and other disorders.³⁰ As of August 2022, only two clinical trials are slated for investigation into new biomarkers for MG.

Although the treatment of MG might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies in coming years.
 

Mr. van der Eb is a second-year candidate in the master’s of science in applied life sciences program, Keck Graduate Institute, Claremont, Calif.; he has an associate’s degree in natural sciences from Pasadena City College, Calif., and a bachelor’s degree in biological sciences from the University of California, Irvine. Ms. Toruno is a graduate from the master’s of science in applied life sciences program, Keck Graduate Institute; she has a bachelor’s degree in psychology, with a minor in biological sciences, from the University of California, Irvine. Dr. Laird is director of clinical education and professor of practice for the master’s of science in physician assistant studies program, Keck Graduate Institute; he practices clinically in general and thoracic surgery.

The authors report no conflict of interest related to this article.

References

1. Gilhus NE et al. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y.

2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.

3. Dresser L et al. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021 May;10(11):2235. doi: 10.3390/jcm10112235.

4. Iyer SR et al. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021 Jul;22(15):8058. doi: 10.3390/ijms22158058.

5. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: Classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018 May;36(2):253-60. doi: 10.1016/j.ncl.2018.01.002.

6. Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021 Dec;21(12):798-813. doi: 10.1038/s41577-021-00543-w.

7. Drachman DB et al. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116-22. doi: 10.1056/NEJM197805182982004.

8. Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108. doi: 10.1159/000212371.

9. Zhang HL, Peng HB. Mechanism of acetylcholine receptor cluster formation induced by DC electric field. PLoS One. 2011;6(10):e26805. doi: 10.1371/journal.pone.0026805.

10. Fichtner ML et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776.

11. Tzartos JS et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-87. doi: 10.1002/acn3.26.

12. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-22. doi: 10.1212/WNL.0000000000011124.

13. Cortés-Vicente E et al. Myasthenia gravis treatment updates. Curr Treat Options Neurol. 2020 Jul 15;22(8):24. doi: 10.1007/s11940-020-00632-6.

14. Tannemaat MR, Verschuuren JJGM. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020 Feb;30(2):111-9. doi: 10.1016/j.nmd.2019.12.003.

15. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014 Jun;15(4):167-78. doi: 10.1097/CND.0000000000000034.

16. Sanders DB et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25. doi: 10.1212/WNL.0000000000002790.

17. Evoli A, Meacci E. An update on thymectomy in myasthenia gravis. Expert Rev Neurother. 2019 Sep;19(9):823-33. doi: 10.1080/14737175.2019.1600404.

18. Habib AA et al. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020 Nov;62(5):579-92. doi: 10.1002/mus.26919.

19. O’Sullivan KE et al. A systematic review of robotic versus open and video assisted thoracoscopic surgery (VATS) approaches for thymectomy. Ann Cardiothorac Surg. 2019 Mar;8(2):174-93. doi: 10.21037/acs.2019.02.04.

20. Wolfe GI et al; MGTX Study Group. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511-22. doi: 10.1056/NEJMoa1602489.

21. Schneider-Gold C et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019 Mar 1;12:1756286419832242. doi: 10.1177/1756286419832242.

22. Howard JF Jr et al; ADAPT Investigator Study Group. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-36. doi: 10.1016/S1474-4422(21)00159-9.

23. U.S. Food and Drug Administration. FDA approves new treatment for myasthenia gravis. News release. Dec 17, 2021. Accessed Feb 21, 2022. http://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis.

24. Ra Pharmaceuticals. A phase 3, multicenter, randomized, double blind, placebo-controlled study to confirm the safety, tolerability, and efficacy of zilucoplan in subjects with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04115293. Updated Jan 28, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04115293.

25. Howard JF Jr et al. Zilucoplan: An investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody–positive generalized myasthenia gravis. Expert Opin Investig Drugs. 2021 May;30(5):483-93. doi: 10.1080/13543784.2021.1897567.

26. Albazli K et al. Complement inhibitor therapy for myasthenia gravis. Front Immunol. 2020 Jun 3;11:917. doi: 10.3389/fimmu.2020.00917.

27. UCB announces positive Phase 3 results for rozanolixizumab in generalized myasthenia gravis. UCB press release. December 10. 2021. Accessed August 15, 2022. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-positive-Phase-3-results-for-rozanolixizumab-in-generalized-myasthenia-gravis.

28. Keller CW et al. Fc-receptor targeted therapies for the treatment of myasthenia gravis. Int J Mol Sci. 2021 May;22(11):5755. doi: 10.3390/ijms22115755.

29. Janssen Research & Development LLC. Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of nipocalimab administered to adults with generalized myasthenia gravis. ClinicalTrials.gov Identifier: NCT04951622. Updated Feb 17, 2022. Accessed Feb 21, 2022. https://clinicaltrials.gov/ct2/show/NCT04951622.

30. Sabre L et al. Circulating miRNAs as potential biomarkers in myasthenia gravis: Tools for personalized medicine. Front Immunol. 2020 Mar 4;11:213. doi: 10.3389/fimmu.2020.00213.


 

The term myasthenia gravis (MG), from the Latin “grave muscle weakness,” denotes the rare autoimmune disorder characterized by dysfunction at the neuromuscular junction.¹ The clinical presentation of the disease is variable but most often includes ocular symptoms, such as ptosis and diplopia, bulbar weakness, and muscle fatigue upon exertion.^2,3 Severe symptoms can lead to myasthenic crisis, in which generalized weakness can affect respiratory muscles, leading to possible intubation or death.^2,3

Onset of disease ranges from childhood to late adulthood, and largely depends on the subgroup of disease and the age of the patient.⁴ Although complications from MG can arise, treatment methods have considerably reduced the risk of MG-associated mortality, with the current rate estimated to be 0.06 to 0.89 deaths for every 1 million person-years (that is, approximately 5% of cases).^3,5
 

Pathophysiology

MG is caused by binding of autoimmune antibodies to postsynaptic receptors and by molecules that prevent signal transduction at the muscle endplate.^2,4,6,7 The main culprit behind the pathology (in approximately 85% of cases) is an autoimmune antibody for the acetylcholine receptor (AChR); however, other offending antibodies – against muscle-specific serine kinases (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), and the proteoglycan agrin – are known, although at a lower frequency (in approximately 15% of cases).^4,8 These antibodies prevent signal transmission by blocking, destroying, or disrupting the clustering of AChR at the muscle endplate, a necessary step in formation of the neuromuscular junction.^4,8,9

• AChR antibody-positive.
• MuSK antibody-positive.
• LRP4 antibody-positive.
• Seronegative MG.

Classifying MG into subgroups gives insight into the functional expectations and potential treatment options for a given patient, although expectations can vary.²

Regrettably, the well-understood pathophysiology, diagnosis, and prognosis of MG have limited investigation and development of new therapies. Additionally, mainstay treatments, such as thymectomy and prednisone, work to alleviate symptoms for most patients, and have also contributed to periods of slowed research and development. However, treatment of refractory MG has, in recent years, become the subject of research on new therapeutic options, aimed at treating heterogeneous disease populations.¹⁰

In this review, we discuss the diagnosis of, and treatment options for, MG, and provide an update on promising options in the therapeutic pipeline.

Diagnosis

Distinguishing MG from other neuromuscular junction disorders is a pertinent step before treatment. Although the biomarkers discussed in this section are sensitive for making a diagnosis of MG, additional research is needed to classify seronegative patients who do not have circulating autoantibodies that are pathognomonic for MG.¹¹

Consensus on treatment standards

A quantitative assessment of best options for treating MG was conducted by leading experts,¹³ who reached consensus that primary outcomes in treating MG are reached when a patient presents without symptoms or limitations on daily activities; or has only slight weakness or fatigue in some muscles.¹³

Emerging therapies

Although conventional treatments for MG are well-established, 10% to 20% of MG patients remain refractory to therapeutic intervention.²¹ These patients are more susceptible to myasthenic crisis, which can result in hospitalization, intubation, and death.²¹ As mentioned, rescue therapies, including plasmapheresis and IVIg, are imperative to achieve remission of refractory MG, but such remission is unsustainable. Risks associated with these therapies, including contraindications and patient comorbidity, and their limited availability have prevented plasmapheresis and IVIg from being reliable interventions.¹²

These shortcomings, along with promising results from randomized clinical trials of newer modes of pharmacotherapeutic intervention, have increased interest in new therapies for MG. For example, complement pathway and neonatal Fc receptor (FcRn) inhibitors have recently shown promise in removing pathogenic autoimmune antibodies.¹⁸

Efgartigimod. FcRn is of interest in treating generalized MG because of its capacity to recycle and extend the half-life of IgG.²² Efgartigimod is a high-affinity FcRn inhibitor that simultaneously reduces IgG recycling and increases its degradation.²² This therapy is unique: it is highly selective for IgG, whereas other FcRn therapies are nonspecific, causing an undesirable decrease in other immunoglobulin and albumin levels.²² In December 2021, the Food and Drug Administration approved efgartigimod for the treatment of AChR-positive generalized MG.²³

Zilucoplan is a subcutaneously administered complement inhibitor that has completed phase 3 clinical trials.^18,24 The drug works by inhibiting cleavage of proteins C5a and C5b in the terminal complement complex, a necessary step in forming cytotoxic pores on targeted cells.^18,24 Zilucoplan also prevents tissue damage and destruction of signal transmission at the postsynaptic membrane.²⁵ Clinical trials have already established improvement in the Quantitative MG Score and the Myasthenia Gravis Activities of Daily Living Score in patients with generalized MG.^18,24

Zilucoplan is similar to eculizumab, but targets a different binding site, allowing for treatment of heterogeneous MG populations who have a mutation in the eculizumab target antigen.²⁶ Additionally, due to specific drug-body interactions, parameters for treatment using zilucoplan are broader than for therapies such as eculizumab. In a Zilucoplan press-release, the complement inhibitor showed statistically significant improvement in the treatment group of generalized, AChR-positive MG patients compared to the placebo group. Tolerability and safety was also a favorable finding in this study. However, a similar rate of treatment-emergent adverse events were recorded between the treatment group (76.7%) and placebo group (70.5%) which could indicate that the clinical application of this treatment is still forthcoming.²⁷ If zilucoplan is approved by the FDA, it will be used earlier in disease progression and for a larger subset of patients.²⁶

Nipocalimab is another immunoglobulin G1, FcRn antibody that reduces IgG levels in blood.^27,28 A phase 2 clinical study in patients with AChR-positive or MuSK antibody–associated MG showed that 52% of patients who received nipocalimab had a significant reduction in the Myasthenia Gravis Activities of Daily Living Score 4 weeks after infusion.²⁸ Phase 3 studies for adults with generalized MG are underway and are expected to conclude in April 2026.²⁹
 

Looking forward

Despite emerging therapies aimed at treating IgG in both refractory and nonrefractory MG, there is still a need for research into biomarkers that further differentiate disease. Developing research into new biomarkers, such as circulating microRNAs, gives insight into the promise of personalized medicine, which can shape the landscape of MG and other disorders.³⁰ As of August 2022, only two clinical trials are slated for investigation into new biomarkers for MG.

Although the treatment of MG might have once been considered stagnant, newer expert consensus and novel research are generating optimism for innovative therapies in coming years.
 

Mr. van der Eb is a second-year candidate in the master’s of science in applied life sciences program, Keck Graduate Institute, Claremont, Calif.; he has an associate’s degree in natural sciences from Pasadena City College, Calif., and a bachelor’s degree in biological sciences from the University of California, Irvine. Ms. Toruno is a graduate from the master’s of science in applied life sciences program, Keck Graduate Institute; she has a bachelor’s degree in psychology, with a minor in biological sciences, from the University of California, Irvine. Dr. Laird is director of clinical education and professor of practice for the master’s of science in physician assistant studies program, Keck Graduate Institute; he practices clinically in general and thoracic surgery.

The authors report no conflict of interest related to this article.

References

1. Gilhus NE et al. Myasthenia gravis. Nat Rev Dis Primers. 2019 May 2;5(1):30. doi: 10.1038/s41572-019-0079-y.

2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: Subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.

3. Dresser L et al. Myasthenia gravis: Epidemiology, pathophysiology and clinical manifestations. J Clin Med. 2021 May;10(11):2235. doi: 10.3390/jcm10112235.

4. Iyer SR et al. The neuromuscular junction: Roles in aging and neuromuscular disease. Int J Mol Sci. 2021 Jul;22(15):8058. doi: 10.3390/ijms22158058.

5. Hehir MK, Silvestri NJ. Generalized myasthenia gravis: Classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018 May;36(2):253-60. doi: 10.1016/j.ncl.2018.01.002.

6. Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021 Dec;21(12):798-813. doi: 10.1038/s41577-021-00543-w.

7. Drachman DB et al. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978 May 18;298(20):1116-22. doi: 10.1056/NEJM197805182982004.

8. Meriggioli MN. Myasthenia gravis with anti-acetylcholine receptor antibodies. Front Neurol Neurosci. 2009;26:94-108. doi: 10.1159/000212371.

9. Zhang HL, Peng HB. Mechanism of acetylcholine receptor cluster formation induced by DC electric field. PLoS One. 2011;6(10):e26805. doi: 10.1371/journal.pone.0026805.

10. Fichtner ML et al. Autoimmune pathology in myasthenia gravis disease subtypes is governed by divergent mechanisms of immunopathology. Front Immunol. 2020 May 27;11:776. doi: 10.3389/fimmu.2020.00776.

11. Tzartos JS et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2014 Feb;1(2):80-87. doi: 10.1002/acn3.26.

12. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology. 2021;96(3):114-22. doi: 10.1212/WNL.0000000000011124.

13. Cortés-Vicente E et al. Myasthenia gravis treatment updates. Curr Treat Options Neurol. 2020 Jul 15;22(8):24. doi: 10.1007/s11940-020-00632-6.

14. Tannemaat MR, Verschuuren JJGM. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020 Feb;30(2):111-9. doi: 10.1016/j.nmd.2019.12.003.

15. Silvestri NJ, Wolfe GI. Treatment-refractory myasthenia gravis. J Clin Neuromuscul Dis. 2014 Jun;15(4):167-78. doi: 10.1097/CND.0000000000000034.

16. Sanders DB et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25. doi: 10.1212/WNL.0000000000002790.

17. Evoli A, Meacci E. An update on thymectomy in myasthenia gravis. Expert Rev Neurother. 2019 Sep;19(9):823-33. doi: 10.1080/14737175.2019.1600404.

18. Habib AA et al. Update on immune-mediated therapies for myasthenia gravis. Muscle Nerve. 2020 Nov;62(5):579-92. doi: 10.1002/mus.26919.

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21. Schneider-Gold C et al. Understanding the burden of refractory myasthenia gravis. Ther Adv Neurol Disord. 2019 Mar 1;12:1756286419832242. doi: 10.1177/1756286419832242.

22. Howard JF Jr et al; ADAPT Investigator Study Group. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): A multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-36. doi: 10.1016/S1474-4422(21)00159-9.

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Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

A version of this article first appeared on Medscape.com.

Cardiac biomarkers vary according to sex hormones in healthy transgender adults, just as in cisgender individuals, a new cross-sectional study suggests.

Previous research in the general population has shown that females have a lower 99th percentile upper reference limit for high-sensitivity cardiac troponin (hs-cTn) than males, whereas N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentrations are higher in females than males across all ages after puberty.

“That trend is similar for people that have been on gender-affirming hormones, saying that sex hormones are playing a role in how cardiac turnover happens in a healthy state,” study author Dina M. Greene, PhD, University of Washington, Seattle, said in an interview.

Although the number of transgender people seeking gender-affirming care is increasing, studies are limited and largely retrospective cohorts, she noted. The scientific literature evaluating and defining cardiac biomarker concentrations is “currently absent.”

The American Heart Association’s recent scientific statement on the cardiovascular health of transgender and gender diverse (TGD) people says mounting evidence points to worse CV health in TGD people and that part of this excess risk is driven by significant psychosocial stressors across the lifespan. “In addition, the use of gender-affirming hormone therapy may be associated with cardiometabolic changes, but health research in this area remains limited and, at times, contradictory.”

For the present study, Dr. Greene and colleagues reached out to LGBTQ-oriented primary care and internal medicine clinics in Seattle and Iowa City to recruit 79 transgender men prescribed testosterone (mean age, 28.8 years) and 93 transgender women (mean age, 35.1 years) prescribed estradiol for at least 12 months. The mean duration of hormone therapy was 4.8 and 3.5 years, respectively.

The median estradiol concentration was 51 pg/mL in transgender men and 207 pg/mL in transgender women. Median testosterone concentrations were 4.6 ng/mL and 0.4 ng/mL, respectively.

The cardiac biomarkers were measured with the ARCHITECT STAT (Abbott Diagnostics) and ACCESS (Beckman Coulter) high-sensitivity troponin I assays, the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics), and the Elecsys ProBNP II immunoassay (Roche Diagnostics).

As reported in JAMA Cardiology, the median hs-cTnI level on the ARCHITECT STAT assay was 0.9 ng/L (range, 0.6-1.7) in transgender men and 0.6 ng/L (range, 0.3-1.0) in transgender women. The pattern was consistent across the two other assays.

In contrast, the median NT-proBNP level was 17 ng/L (range, 13-27) in transgender men and 49 ng/L (range, 32-86) in transgender women.

“It seems that sex hormone concentration is a stronger driver of baseline cardiac troponin and NT-proBNP concentrations relative to sex assigned at birth,” Dr. Greene said.

The observed differences in hs-cTn concentrations “are likely physiological and not pathological,” given that concentrations between healthy cisgender people are also apparent and not thought to portend adverse events, the authors noted.

Teasing out the clinical implications of sex-specific hs-cTn upper reference limits for ruling in acute myocardial infarction (MI), however, is complicated by biological and social factors that contribute to poorer outcomes in women, despite lower baseline levels, they added. “Ultimately, the psychosocial benefits of gender-affirming hormones are substantial, and informed consent is likely the ideal method to balance the undetermined risks.”

Dr. Greene pointed out that the study wasn’t powered to accurately calculate gender-specific hs-cTn 99th percentiles or reference intervals for NT-proBNP and assessed the biomarkers at a single time point.

For the transgender person presenting with chest pain, she said, the clinical implications are not yet known, but the data suggest that when sex-specific 99th percentiles for hs-cTn are used, the numeric value associated with the affirmed gender, rather than the sex assigned at birth, may be the appropriate URL.

“It really depends on what the triage pathway is and if that pathway has differences for people of different sexes and how often people get serial measurements,” Dr. Greene said. “Within this population, it’s very important to look at those serial measurements because for people that are not cismen, those 99th percentiles when they’re non–sex specific, are going to favor in detection of a heart attack. So, you need to look at the second value to make sure there hasn’t been a change over time.”

The observed differences in the distribution of NT-proBNP concentrations is similar to that in the cisgender population, Dr. Greene noted. But these differences do not lead to sex-specific diagnostic thresholds because of the significant elevations present in overt heart failure and cardiovascular disease. “For NT-proBNP, it’s not as important. People don’t usually have a little bit of heart failure, they have heart failure, where people have small MIs.”

Dr. Greene said she would like to see larger trials looking at biomarker measurements and cardiac imaging before hormone therapy but that the biggest issue is the need for inclusion of transgender people in all cardiovascular trials.

“The sample sizes are never going to be as big as we get for cisgender people for a number of reasons but ensuring that it’s something that’s being asked on intake and monitored over time so we can understand how transgender people fit into the general population for cardiac disease,” Dr. Greene said. “And so, we can normalize that they exist. I keep driving this point home, but this is the biggest thing right now when it’s such a political issue.”

The study was supported in part by the department of laboratory medicine at the University of Washington, the department of pathology at the University of Iowa, and a grant from Abbott Diagnostics for in-kind high-sensitivity cardiac troponin I reagent. One coauthor reported financial relationships with Siemens Healthineers, Roche Diagnostics, Beckman Coulter, Becton, Dickinson, Abbott Diagnostics, Quidel Diagnostics, Sphingotech, and PixCell Medical. No other disclosures were reported.

A version of this article first appeared on Medscape.com.