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Improvements needed in SCD care, report says
Photo courtesy of St. Jude
Children’s Hospital
A new report suggests the current state of care for sickle cell disease (SCD) is inadequate, and improvements are needed.
The State of Sickle Cell Disease: 2016 Report outlines 4 main areas for improvement—SCD patients’ access to care, the training and education of healthcare professionals treating patients with SCD, research and clinical trials pertaining to SCD, and global health issues related to the disease.
The American Society of Hematology (ASH) published the report, with the endorsement of organizations in the SCD community.
The report includes statistics that highlight the need for improvements as well as future goals and recommended actions.
Access to care
The report states that more than 75% of adults with SCD who have frequent pain crises do not receive the recommended treatment, hydroxyurea.
One potential solution, according to the report, is to ensure that existing standard-of-care guidelines are being used. Another solution is to develop coordinated healthcare delivery models that ensure SCD patients can access quality care regardless of their age, location, and socioeconomic status.
“Not only are individuals with SCD burdened by the pain and disability that comes with a chronic condition, but they also have very few accessible treatment options due to our fragmented healthcare system,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
Training and education
The report cites a national survey in which only 20.4% of family physicians said they felt comfortable treating SCD. And 69.4% of family physicians said clinical decision support tools would be useful for helping to guide their treatment decisions for SCD patients.
Therefore, the report recommends devising an “actionable plan” to educate healthcare providers about best practices in caring for SCD patients, developing clinical support tools, and encouraging medical trainees to pursue careers in SCD care, among other solutions.
“There are many unique challenges that people with SCD face,” said ASH Vice President Alexis Thompson, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.
“For example, the transition from pediatric to adult care can be especially difficult, and many people struggle to find healthcare providers with comprehensive knowledge and expertise to provide proper care, especially in rural communities.”
Research and clinical trials
The report notes that hydroxyurea is the only drug approved by the US Food and Drug Administration to treat SCD. Therefore, research is needed to develop novel therapies, new drug delivery modes, and new agents that can be used in combination with hydroxyurea.
The report also highlights other areas where research is needed and recommends developing clinical trial networks to increase enrollment in trials.
Global issues
According to the report, roughly 1000 children in Africa are born with SCD every day, and more than half will die before they reach the age of 5. In addition, more than 90% of children with SCD who live in resource-poor countries do not survive to adulthood.
Therefore, the report recommends expanding newborn screening and early intervention programs, increasing SCD awareness and education, and improving access to quality care in developing regions.
Sickle Cell Disease Coalition
To address the aforementioned challenges, ASH and more than 20 other organizations launched the Sickle Cell Disease Coalition. The coalition is focused on promoting research, clinical care, education, training, and advocacy.
The aim of the coalition is to provide a platform to encourage stakeholders to work together to implement projects and activities that will ultimately help the SCD community and improve patient outcomes.
The coalition consists of leading patient advocacy groups, people with SCD and their families, researchers, clinicians, policymakers, industry stakeholders, and foundations with an interest in SCD. 
Photo courtesy of St. Jude
Children’s Hospital
A new report suggests the current state of care for sickle cell disease (SCD) is inadequate, and improvements are needed.
The State of Sickle Cell Disease: 2016 Report outlines 4 main areas for improvement—SCD patients’ access to care, the training and education of healthcare professionals treating patients with SCD, research and clinical trials pertaining to SCD, and global health issues related to the disease.
The American Society of Hematology (ASH) published the report, with the endorsement of organizations in the SCD community.
The report includes statistics that highlight the need for improvements as well as future goals and recommended actions.
Access to care
The report states that more than 75% of adults with SCD who have frequent pain crises do not receive the recommended treatment, hydroxyurea.
One potential solution, according to the report, is to ensure that existing standard-of-care guidelines are being used. Another solution is to develop coordinated healthcare delivery models that ensure SCD patients can access quality care regardless of their age, location, and socioeconomic status.
“Not only are individuals with SCD burdened by the pain and disability that comes with a chronic condition, but they also have very few accessible treatment options due to our fragmented healthcare system,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
Training and education
The report cites a national survey in which only 20.4% of family physicians said they felt comfortable treating SCD. And 69.4% of family physicians said clinical decision support tools would be useful for helping to guide their treatment decisions for SCD patients.
Therefore, the report recommends devising an “actionable plan” to educate healthcare providers about best practices in caring for SCD patients, developing clinical support tools, and encouraging medical trainees to pursue careers in SCD care, among other solutions.
“There are many unique challenges that people with SCD face,” said ASH Vice President Alexis Thompson, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.
“For example, the transition from pediatric to adult care can be especially difficult, and many people struggle to find healthcare providers with comprehensive knowledge and expertise to provide proper care, especially in rural communities.”
Research and clinical trials
The report notes that hydroxyurea is the only drug approved by the US Food and Drug Administration to treat SCD. Therefore, research is needed to develop novel therapies, new drug delivery modes, and new agents that can be used in combination with hydroxyurea.
The report also highlights other areas where research is needed and recommends developing clinical trial networks to increase enrollment in trials.
Global issues
According to the report, roughly 1000 children in Africa are born with SCD every day, and more than half will die before they reach the age of 5. In addition, more than 90% of children with SCD who live in resource-poor countries do not survive to adulthood.
Therefore, the report recommends expanding newborn screening and early intervention programs, increasing SCD awareness and education, and improving access to quality care in developing regions.
Sickle Cell Disease Coalition
To address the aforementioned challenges, ASH and more than 20 other organizations launched the Sickle Cell Disease Coalition. The coalition is focused on promoting research, clinical care, education, training, and advocacy.
The aim of the coalition is to provide a platform to encourage stakeholders to work together to implement projects and activities that will ultimately help the SCD community and improve patient outcomes.
The coalition consists of leading patient advocacy groups, people with SCD and their families, researchers, clinicians, policymakers, industry stakeholders, and foundations with an interest in SCD.
Photo courtesy of St. Jude
Children’s Hospital
A new report suggests the current state of care for sickle cell disease (SCD) is inadequate, and improvements are needed.
The State of Sickle Cell Disease: 2016 Report outlines 4 main areas for improvement—SCD patients’ access to care, the training and education of healthcare professionals treating patients with SCD, research and clinical trials pertaining to SCD, and global health issues related to the disease.
The American Society of Hematology (ASH) published the report, with the endorsement of organizations in the SCD community.
The report includes statistics that highlight the need for improvements as well as future goals and recommended actions.
Access to care
The report states that more than 75% of adults with SCD who have frequent pain crises do not receive the recommended treatment, hydroxyurea.
One potential solution, according to the report, is to ensure that existing standard-of-care guidelines are being used. Another solution is to develop coordinated healthcare delivery models that ensure SCD patients can access quality care regardless of their age, location, and socioeconomic status.
“Not only are individuals with SCD burdened by the pain and disability that comes with a chronic condition, but they also have very few accessible treatment options due to our fragmented healthcare system,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
Training and education
The report cites a national survey in which only 20.4% of family physicians said they felt comfortable treating SCD. And 69.4% of family physicians said clinical decision support tools would be useful for helping to guide their treatment decisions for SCD patients.
Therefore, the report recommends devising an “actionable plan” to educate healthcare providers about best practices in caring for SCD patients, developing clinical support tools, and encouraging medical trainees to pursue careers in SCD care, among other solutions.
“There are many unique challenges that people with SCD face,” said ASH Vice President Alexis Thompson, MD, of the Ann and Robert H. Lurie Children’s Hospital of Chicago in Illinois.
“For example, the transition from pediatric to adult care can be especially difficult, and many people struggle to find healthcare providers with comprehensive knowledge and expertise to provide proper care, especially in rural communities.”
Research and clinical trials
The report notes that hydroxyurea is the only drug approved by the US Food and Drug Administration to treat SCD. Therefore, research is needed to develop novel therapies, new drug delivery modes, and new agents that can be used in combination with hydroxyurea.
The report also highlights other areas where research is needed and recommends developing clinical trial networks to increase enrollment in trials.
Global issues
According to the report, roughly 1000 children in Africa are born with SCD every day, and more than half will die before they reach the age of 5. In addition, more than 90% of children with SCD who live in resource-poor countries do not survive to adulthood.
Therefore, the report recommends expanding newborn screening and early intervention programs, increasing SCD awareness and education, and improving access to quality care in developing regions.
Sickle Cell Disease Coalition
To address the aforementioned challenges, ASH and more than 20 other organizations launched the Sickle Cell Disease Coalition. The coalition is focused on promoting research, clinical care, education, training, and advocacy.
The aim of the coalition is to provide a platform to encourage stakeholders to work together to implement projects and activities that will ultimately help the SCD community and improve patient outcomes.
The coalition consists of leading patient advocacy groups, people with SCD and their families, researchers, clinicians, policymakers, industry stakeholders, and foundations with an interest in SCD.
Study supports expanded prenatal genetic testing
Photo by Nina Matthews
New research suggests expanded prenatal genetic testing may increase the detection of carrier status for potentially serious genetic conditions, including hemoglobinopathies.
Researchers analyzed nearly 350,000 adults of diverse racial and ethnic backgrounds and found evidence to suggest that expanded screening for up to 94 conditions can increase the detection of carrier status when compared with current genetic testing recommendations from professional societies.
Imran S. Haque, PhD, of Counsyl in San Francisco, California, and his colleagues reported these findings in JAMA. The study was funded by Counsyl, a laboratory providing expanded carrier screening.
Genetic testing of prospective parents to detect carriers of specific inherited recessive diseases is part of routine obstetrical practice. The current recommendations are to test for a limited number of individual diseases, in part based on self-reported racial/ethnic background.
Dr Haque and his colleagues wanted to determine if recent advances in genetic testing could facilitate screening for an expanded number of conditions independent of racial/ethnic background.
The researchers analyzed results from expanded carrier screening in 346,790 reproductive-aged individuals, primarily from the US, without known indication for specific genetic testing.
The individuals were tested for carrier status for up to 94 conditions. Tests were offered by clinicians providing reproductive care.
Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease.
Severe conditions were defined as those that, if left untreated, cause intellectual disability or a substantially shortened lifespan. Profound conditions were those causing both intellectual disability and a shortened lifespan.
The researchers found that, in most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines.
Overall, relative to expanded carrier screening, guideline-based screening ranged from identifying 6% of hypothetical fetuses affected for East Asian couples to 87% for African or African American couples.
Though this study suggests expanded screening could be beneficial, the researchers said their findings should be confirmed with prospective studies comparing current carrier screening with expanded screening in at-risk populations.
Photo by Nina Matthews
New research suggests expanded prenatal genetic testing may increase the detection of carrier status for potentially serious genetic conditions, including hemoglobinopathies.
Researchers analyzed nearly 350,000 adults of diverse racial and ethnic backgrounds and found evidence to suggest that expanded screening for up to 94 conditions can increase the detection of carrier status when compared with current genetic testing recommendations from professional societies.
Imran S. Haque, PhD, of Counsyl in San Francisco, California, and his colleagues reported these findings in JAMA. The study was funded by Counsyl, a laboratory providing expanded carrier screening.
Genetic testing of prospective parents to detect carriers of specific inherited recessive diseases is part of routine obstetrical practice. The current recommendations are to test for a limited number of individual diseases, in part based on self-reported racial/ethnic background.
Dr Haque and his colleagues wanted to determine if recent advances in genetic testing could facilitate screening for an expanded number of conditions independent of racial/ethnic background.
The researchers analyzed results from expanded carrier screening in 346,790 reproductive-aged individuals, primarily from the US, without known indication for specific genetic testing.
The individuals were tested for carrier status for up to 94 conditions. Tests were offered by clinicians providing reproductive care.
Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease.
Severe conditions were defined as those that, if left untreated, cause intellectual disability or a substantially shortened lifespan. Profound conditions were those causing both intellectual disability and a shortened lifespan.
The researchers found that, in most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines.
Overall, relative to expanded carrier screening, guideline-based screening ranged from identifying 6% of hypothetical fetuses affected for East Asian couples to 87% for African or African American couples.
Though this study suggests expanded screening could be beneficial, the researchers said their findings should be confirmed with prospective studies comparing current carrier screening with expanded screening in at-risk populations.
Photo by Nina Matthews
New research suggests expanded prenatal genetic testing may increase the detection of carrier status for potentially serious genetic conditions, including hemoglobinopathies.
Researchers analyzed nearly 350,000 adults of diverse racial and ethnic backgrounds and found evidence to suggest that expanded screening for up to 94 conditions can increase the detection of carrier status when compared with current genetic testing recommendations from professional societies.
Imran S. Haque, PhD, of Counsyl in San Francisco, California, and his colleagues reported these findings in JAMA. The study was funded by Counsyl, a laboratory providing expanded carrier screening.
Genetic testing of prospective parents to detect carriers of specific inherited recessive diseases is part of routine obstetrical practice. The current recommendations are to test for a limited number of individual diseases, in part based on self-reported racial/ethnic background.
Dr Haque and his colleagues wanted to determine if recent advances in genetic testing could facilitate screening for an expanded number of conditions independent of racial/ethnic background.
The researchers analyzed results from expanded carrier screening in 346,790 reproductive-aged individuals, primarily from the US, without known indication for specific genetic testing.
The individuals were tested for carrier status for up to 94 conditions. Tests were offered by clinicians providing reproductive care.
Risk was defined as the probability that a hypothetical fetus created from a random pairing of individuals (within or across 15 self-reported racial/ethnic categories) would be homozygous or compound heterozygous for 2 mutations presumed to cause severe or profound disease.
Severe conditions were defined as those that, if left untreated, cause intellectual disability or a substantially shortened lifespan. Profound conditions were those causing both intellectual disability and a shortened lifespan.
The researchers found that, in most racial/ethnic categories, expanded carrier screening modeled more hypothetical fetuses at risk for severe or profound conditions than did screening based on current professional guidelines.
Overall, relative to expanded carrier screening, guideline-based screening ranged from identifying 6% of hypothetical fetuses affected for East Asian couples to 87% for African or African American couples.
Though this study suggests expanded screening could be beneficial, the researchers said their findings should be confirmed with prospective studies comparing current carrier screening with expanded screening in at-risk populations.
Drug granted orphan designation for MAS
Image from Flickr
The US Food and Drug Administration (FDA) has granted orphan drug designation for dusquetide as a treatment for macrophage activation syndrome (MAS).
Dusquetide is an innate defense regulator, a new class of short, synthetic peptides that accelerate bacterial clearance and resolution of tissue damage while modulating inflammation following exposure to bacterial pathogens, radiation, chemotherapy, and other agents.
According to researchers, dusquetide has demonstrated preclinical efficacy and safety in several animal models.
In a mouse model of MAS, dusquetide was shown to reduce pancytopenia, inhibit IL-12 responses, and improve body weight maintenance.
SGX942, the drug product containing dusquetide, has demonstrated safety in a phase 1 study of 84 healthy volunteers.
In addition, SGX942 has demonstrated preliminary efficacy and safety in an exploratory phase 2 study of 111 patients with oral mucositis due to chemoradiation therapy for head and neck cancer.
SGX942 is being developed by Solgenix, Inc.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
About MAS
MAS is a life-threatening complication of rheumatic disease that, for unknown reasons, frequently occurs in individuals with systemic juvenile idiopathic arthritis. MAS also occurs in patients with systemic lupus erythematosus, Kawasaki disease, adult-onset Still’s disease, and various vasculitic syndromes.
MAS is characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms.
MAS is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction.
Image from Flickr
The US Food and Drug Administration (FDA) has granted orphan drug designation for dusquetide as a treatment for macrophage activation syndrome (MAS).
Dusquetide is an innate defense regulator, a new class of short, synthetic peptides that accelerate bacterial clearance and resolution of tissue damage while modulating inflammation following exposure to bacterial pathogens, radiation, chemotherapy, and other agents.
According to researchers, dusquetide has demonstrated preclinical efficacy and safety in several animal models.
In a mouse model of MAS, dusquetide was shown to reduce pancytopenia, inhibit IL-12 responses, and improve body weight maintenance.
SGX942, the drug product containing dusquetide, has demonstrated safety in a phase 1 study of 84 healthy volunteers.
In addition, SGX942 has demonstrated preliminary efficacy and safety in an exploratory phase 2 study of 111 patients with oral mucositis due to chemoradiation therapy for head and neck cancer.
SGX942 is being developed by Solgenix, Inc.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
About MAS
MAS is a life-threatening complication of rheumatic disease that, for unknown reasons, frequently occurs in individuals with systemic juvenile idiopathic arthritis. MAS also occurs in patients with systemic lupus erythematosus, Kawasaki disease, adult-onset Still’s disease, and various vasculitic syndromes.
MAS is characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms.
MAS is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction.
Image from Flickr
The US Food and Drug Administration (FDA) has granted orphan drug designation for dusquetide as a treatment for macrophage activation syndrome (MAS).
Dusquetide is an innate defense regulator, a new class of short, synthetic peptides that accelerate bacterial clearance and resolution of tissue damage while modulating inflammation following exposure to bacterial pathogens, radiation, chemotherapy, and other agents.
According to researchers, dusquetide has demonstrated preclinical efficacy and safety in several animal models.
In a mouse model of MAS, dusquetide was shown to reduce pancytopenia, inhibit IL-12 responses, and improve body weight maintenance.
SGX942, the drug product containing dusquetide, has demonstrated safety in a phase 1 study of 84 healthy volunteers.
In addition, SGX942 has demonstrated preliminary efficacy and safety in an exploratory phase 2 study of 111 patients with oral mucositis due to chemoradiation therapy for head and neck cancer.
SGX942 is being developed by Solgenix, Inc.
About orphan designation
The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the drug is approved.
About MAS
MAS is a life-threatening complication of rheumatic disease that, for unknown reasons, frequently occurs in individuals with systemic juvenile idiopathic arthritis. MAS also occurs in patients with systemic lupus erythematosus, Kawasaki disease, adult-onset Still’s disease, and various vasculitic syndromes.
MAS is characterized by pancytopenia, liver insufficiency, coagulopathy, and neurologic symptoms.
MAS is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and well-differentiated macrophages, leading to widespread hemophagocytosis and cytokine overproduction.
Potential treatment strategy for dyskeratosis congenita
Preclinical research has revealed a potential treatment strategy for dyskeratosis congenita (DC).
Researchers found that DC is characterized by reductions in telomerase, telomere length, and telomere capping, which reduces Wnt pathway activity, resulting in intestinal stem cell failure.
However, treatment with Wnt agonists restored the Wnt-telomere feedback loop and reversed gastrointestinal DC phenotypes in vitro and in vivo.
Christopher J. Lengner, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these discoveries in Cell Stem Cell.
“Right now, the main therapy for [DC] patients is a bone marrow transplant,” Dr Lengner said. “That can address the bone marrow failure but doesn’t fix other problems associated with the disease, and especially not the risk of cancer. This work suggests a way to address the underlying cause of the disease.”
Earlier research with mouse models of DC suggested there might be a connection between the Wnt pathway and telomerase. And a recent study in DC patients’ cells revealed a decrease in activity in the Wnt pathway.
So Dr Lengner and his colleagues wanted to explore whether activating Wnt could reverse the effects of the disease. To do so, the team used induced pluripotent stem cells (iPSCs), the CRISPR/Cas9 gene-editing system, and directed differentiation.
The researchers generated iPSCs from DKC1-mutant fibroblasts and from wild-type cells. The team also used CRISPR to introduce a DKC1 mutation into healthy human iPSCs and to correct the disease-causing mutation in iPSCs generated from DC patient samples.
The researchers then grew organoids through directed differentiation. iPSCs were coaxed to form a human intestinal organoid, which naturally forms a tube-like structure, recapitulating the tubes of the human gastrointestinal system.
When the researchers observed the development of intestinal organoids, they found that, initially, the DC cells seemed to form normally.
The original DKC1-mutant cells and the cells that had the DKC1 mutation introduced by CRISPR appeared to follow a normal course of development for several days. But by 2 weeks, they lacked the tube-like structure seen in the healthy samples and the disease-corrected samples.
The DKC1-mutant cells also had shorter telomeres, with the intestinal organoids from DC patients having the shortest of any cell type.
“We could see, at the molecular level, that this is accompanied by a failure to activate specific intestinal stem cell gene programs—specifically, genes in the Wnt pathway,” Dr Lengner said.
The next logical step was to activate Wnt to see if these defects could be reversed. The researchers treated organoids derived from DC patient iPSCs with a compound called CHIR that stimulates the Wnt pathway.
This restored the formation of the tube-like structure as well as intestinal stem cell gene expression. The treatment also increased telomerase activity and telomere length in the cells with mutant DKC1.
To assess this treatment approach in a more clinically relevant model, the researchers transplanted the human intestinal organoids into mice.
Mice that received a transplant containing the DKC1 mutation and received treatment with lithium, a stimulator of the Wnt pathway, maintained their intestinal tissue structure and had high expression of Wnt target genes.
In effect, these mice resembled the mice that received a transplant of an organoid derived from a healthy patient.
The researchers said this study offers proof of principle that activating the Wnt pathway can reverse at least the gastrointestinal phenotypes associated with DC. Looking ahead, the team would like to try accomplishing the same feat in other tissue types affected by the disease.
Preclinical research has revealed a potential treatment strategy for dyskeratosis congenita (DC).
Researchers found that DC is characterized by reductions in telomerase, telomere length, and telomere capping, which reduces Wnt pathway activity, resulting in intestinal stem cell failure.
However, treatment with Wnt agonists restored the Wnt-telomere feedback loop and reversed gastrointestinal DC phenotypes in vitro and in vivo.
Christopher J. Lengner, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these discoveries in Cell Stem Cell.
“Right now, the main therapy for [DC] patients is a bone marrow transplant,” Dr Lengner said. “That can address the bone marrow failure but doesn’t fix other problems associated with the disease, and especially not the risk of cancer. This work suggests a way to address the underlying cause of the disease.”
Earlier research with mouse models of DC suggested there might be a connection between the Wnt pathway and telomerase. And a recent study in DC patients’ cells revealed a decrease in activity in the Wnt pathway.
So Dr Lengner and his colleagues wanted to explore whether activating Wnt could reverse the effects of the disease. To do so, the team used induced pluripotent stem cells (iPSCs), the CRISPR/Cas9 gene-editing system, and directed differentiation.
The researchers generated iPSCs from DKC1-mutant fibroblasts and from wild-type cells. The team also used CRISPR to introduce a DKC1 mutation into healthy human iPSCs and to correct the disease-causing mutation in iPSCs generated from DC patient samples.
The researchers then grew organoids through directed differentiation. iPSCs were coaxed to form a human intestinal organoid, which naturally forms a tube-like structure, recapitulating the tubes of the human gastrointestinal system.
When the researchers observed the development of intestinal organoids, they found that, initially, the DC cells seemed to form normally.
The original DKC1-mutant cells and the cells that had the DKC1 mutation introduced by CRISPR appeared to follow a normal course of development for several days. But by 2 weeks, they lacked the tube-like structure seen in the healthy samples and the disease-corrected samples.
The DKC1-mutant cells also had shorter telomeres, with the intestinal organoids from DC patients having the shortest of any cell type.
“We could see, at the molecular level, that this is accompanied by a failure to activate specific intestinal stem cell gene programs—specifically, genes in the Wnt pathway,” Dr Lengner said.
The next logical step was to activate Wnt to see if these defects could be reversed. The researchers treated organoids derived from DC patient iPSCs with a compound called CHIR that stimulates the Wnt pathway.
This restored the formation of the tube-like structure as well as intestinal stem cell gene expression. The treatment also increased telomerase activity and telomere length in the cells with mutant DKC1.
To assess this treatment approach in a more clinically relevant model, the researchers transplanted the human intestinal organoids into mice.
Mice that received a transplant containing the DKC1 mutation and received treatment with lithium, a stimulator of the Wnt pathway, maintained their intestinal tissue structure and had high expression of Wnt target genes.
In effect, these mice resembled the mice that received a transplant of an organoid derived from a healthy patient.
The researchers said this study offers proof of principle that activating the Wnt pathway can reverse at least the gastrointestinal phenotypes associated with DC. Looking ahead, the team would like to try accomplishing the same feat in other tissue types affected by the disease.
Preclinical research has revealed a potential treatment strategy for dyskeratosis congenita (DC).
Researchers found that DC is characterized by reductions in telomerase, telomere length, and telomere capping, which reduces Wnt pathway activity, resulting in intestinal stem cell failure.
However, treatment with Wnt agonists restored the Wnt-telomere feedback loop and reversed gastrointestinal DC phenotypes in vitro and in vivo.
Christopher J. Lengner, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these discoveries in Cell Stem Cell.
“Right now, the main therapy for [DC] patients is a bone marrow transplant,” Dr Lengner said. “That can address the bone marrow failure but doesn’t fix other problems associated with the disease, and especially not the risk of cancer. This work suggests a way to address the underlying cause of the disease.”
Earlier research with mouse models of DC suggested there might be a connection between the Wnt pathway and telomerase. And a recent study in DC patients’ cells revealed a decrease in activity in the Wnt pathway.
So Dr Lengner and his colleagues wanted to explore whether activating Wnt could reverse the effects of the disease. To do so, the team used induced pluripotent stem cells (iPSCs), the CRISPR/Cas9 gene-editing system, and directed differentiation.
The researchers generated iPSCs from DKC1-mutant fibroblasts and from wild-type cells. The team also used CRISPR to introduce a DKC1 mutation into healthy human iPSCs and to correct the disease-causing mutation in iPSCs generated from DC patient samples.
The researchers then grew organoids through directed differentiation. iPSCs were coaxed to form a human intestinal organoid, which naturally forms a tube-like structure, recapitulating the tubes of the human gastrointestinal system.
When the researchers observed the development of intestinal organoids, they found that, initially, the DC cells seemed to form normally.
The original DKC1-mutant cells and the cells that had the DKC1 mutation introduced by CRISPR appeared to follow a normal course of development for several days. But by 2 weeks, they lacked the tube-like structure seen in the healthy samples and the disease-corrected samples.
The DKC1-mutant cells also had shorter telomeres, with the intestinal organoids from DC patients having the shortest of any cell type.
“We could see, at the molecular level, that this is accompanied by a failure to activate specific intestinal stem cell gene programs—specifically, genes in the Wnt pathway,” Dr Lengner said.
The next logical step was to activate Wnt to see if these defects could be reversed. The researchers treated organoids derived from DC patient iPSCs with a compound called CHIR that stimulates the Wnt pathway.
This restored the formation of the tube-like structure as well as intestinal stem cell gene expression. The treatment also increased telomerase activity and telomere length in the cells with mutant DKC1.
To assess this treatment approach in a more clinically relevant model, the researchers transplanted the human intestinal organoids into mice.
Mice that received a transplant containing the DKC1 mutation and received treatment with lithium, a stimulator of the Wnt pathway, maintained their intestinal tissue structure and had high expression of Wnt target genes.
In effect, these mice resembled the mice that received a transplant of an organoid derived from a healthy patient.
The researchers said this study offers proof of principle that activating the Wnt pathway can reverse at least the gastrointestinal phenotypes associated with DC. Looking ahead, the team would like to try accomplishing the same feat in other tissue types affected by the disease.
Anemia linked to risk of death after stroke
Anemia may increase the risk of death in older adults who have had a stroke, according to research published in the Journal of the American Heart Association.
An initial analysis of more than 8000 patients showed that anemia was associated with a higher risk of death for up to 1 year following ischemic or hemorrhagic stroke.
A second analysis of nearly 30,000 patients suggested the risk of dying from ischemic stroke is about 2 times higher in patients with anemia than those without it, and the risk of death from hemorrhagic stroke is about 1.5 times higher in anemic patients.
“So there’s the potential for a much poorer outcome if somebody comes in with stroke and they’re also anemic,” said study author Phyo Myint, MD, of the University of Aberdeen in Scotland.
Dr Myint and his colleagues first examined data from the UK Regional Stroke Register. This included 8013 patients with an average age of 78 who were admitted to the hospital with acute stroke between 2003 and 2015.
The team assessed the impact of anemia and hemoglobin levels at admission on death at different time points—inpatient, 7 days, 14 days, 1 month, 3 months, 6 months, and 1 year after stroke.
Anemia was associated with higher odds of death at most of the time points examined. And elevated hemoglobin was associated with a higher risk of death, mainly within the first month.
In addition to analyzing data from the UK Regional Stroke Registry, the researchers systematically reviewed relevant literature published to date. They compiled data from 20 previous studies, increasing the study population to 29,943 stroke patients.
In analyzing these patients, the researchers found that anemia on admission was associated with an increased risk of mortality in both ischemic stroke and hemorrhagic stroke. The odds ratios were 1.97 and 1.46, respectively.
The researchers believe this study emphasizes the impact of anemia on stroke outcomes and the need for increased awareness and interventions for stroke patients with anemia.
“One example of an intervention might be treating the underlying causes of anemia, such as iron deficiency, which is common in this age group,” said study author Raphae Barlas, a medical student at the University of Aberdeen.
“As the study has convincingly demonstrated, anemia does worsen the outcome of stroke, so it is very important that we identify at-risk patients and optimize the management.”
Anemia may increase the risk of death in older adults who have had a stroke, according to research published in the Journal of the American Heart Association.
An initial analysis of more than 8000 patients showed that anemia was associated with a higher risk of death for up to 1 year following ischemic or hemorrhagic stroke.
A second analysis of nearly 30,000 patients suggested the risk of dying from ischemic stroke is about 2 times higher in patients with anemia than those without it, and the risk of death from hemorrhagic stroke is about 1.5 times higher in anemic patients.
“So there’s the potential for a much poorer outcome if somebody comes in with stroke and they’re also anemic,” said study author Phyo Myint, MD, of the University of Aberdeen in Scotland.
Dr Myint and his colleagues first examined data from the UK Regional Stroke Register. This included 8013 patients with an average age of 78 who were admitted to the hospital with acute stroke between 2003 and 2015.
The team assessed the impact of anemia and hemoglobin levels at admission on death at different time points—inpatient, 7 days, 14 days, 1 month, 3 months, 6 months, and 1 year after stroke.
Anemia was associated with higher odds of death at most of the time points examined. And elevated hemoglobin was associated with a higher risk of death, mainly within the first month.
In addition to analyzing data from the UK Regional Stroke Registry, the researchers systematically reviewed relevant literature published to date. They compiled data from 20 previous studies, increasing the study population to 29,943 stroke patients.
In analyzing these patients, the researchers found that anemia on admission was associated with an increased risk of mortality in both ischemic stroke and hemorrhagic stroke. The odds ratios were 1.97 and 1.46, respectively.
The researchers believe this study emphasizes the impact of anemia on stroke outcomes and the need for increased awareness and interventions for stroke patients with anemia.
“One example of an intervention might be treating the underlying causes of anemia, such as iron deficiency, which is common in this age group,” said study author Raphae Barlas, a medical student at the University of Aberdeen.
“As the study has convincingly demonstrated, anemia does worsen the outcome of stroke, so it is very important that we identify at-risk patients and optimize the management.”
Anemia may increase the risk of death in older adults who have had a stroke, according to research published in the Journal of the American Heart Association.
An initial analysis of more than 8000 patients showed that anemia was associated with a higher risk of death for up to 1 year following ischemic or hemorrhagic stroke.
A second analysis of nearly 30,000 patients suggested the risk of dying from ischemic stroke is about 2 times higher in patients with anemia than those without it, and the risk of death from hemorrhagic stroke is about 1.5 times higher in anemic patients.
“So there’s the potential for a much poorer outcome if somebody comes in with stroke and they’re also anemic,” said study author Phyo Myint, MD, of the University of Aberdeen in Scotland.
Dr Myint and his colleagues first examined data from the UK Regional Stroke Register. This included 8013 patients with an average age of 78 who were admitted to the hospital with acute stroke between 2003 and 2015.
The team assessed the impact of anemia and hemoglobin levels at admission on death at different time points—inpatient, 7 days, 14 days, 1 month, 3 months, 6 months, and 1 year after stroke.
Anemia was associated with higher odds of death at most of the time points examined. And elevated hemoglobin was associated with a higher risk of death, mainly within the first month.
In addition to analyzing data from the UK Regional Stroke Registry, the researchers systematically reviewed relevant literature published to date. They compiled data from 20 previous studies, increasing the study population to 29,943 stroke patients.
In analyzing these patients, the researchers found that anemia on admission was associated with an increased risk of mortality in both ischemic stroke and hemorrhagic stroke. The odds ratios were 1.97 and 1.46, respectively.
The researchers believe this study emphasizes the impact of anemia on stroke outcomes and the need for increased awareness and interventions for stroke patients with anemia.
“One example of an intervention might be treating the underlying causes of anemia, such as iron deficiency, which is common in this age group,” said study author Raphae Barlas, a medical student at the University of Aberdeen.
“As the study has convincingly demonstrated, anemia does worsen the outcome of stroke, so it is very important that we identify at-risk patients and optimize the management.”
Genome-editing approach could treat SCD
and a sickled one
Image by Betty Pace
CRISPR-Cas9-mediated genome editing might be a feasible approach for treating sickle cell disease (SCD), according to a group of researchers.
The team used CRISPR to edit hematopoietic stem and progenitor cells (HSPCs) from patients with SCD, which resulted in the production of red blood cells (RBCs) that had enough fetal hemoglobin to be healthy.
The researchers believe this approach might prove effective in treating beta-thalassemia as well.
“Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin,” said study author Mitchell J. Weiss, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia . . . . We have found a way to use CRISPR gene editing to produce similar benefits.”
Dr Weiss and his colleagues described this method in Nature Medicine.
The researchers noted that SCD and beta-thalassemia become symptomatic when fetal gamma-globin expression from 2 genes, HBG1 and HBG2, decreases and the expression of adult beta-globin increases, which shifts RBC hemoglobin from the fetal form to the adult form.
Reversing this shift can raise levels of fetal hemoglobin and ameliorate the symptoms of beta-thalassemia or SCD.
The team also pointed out that, in people with a benign genetic condition known as hereditary persistence of fetal hemoglobin (HPFH), mutations attenuate gamma-globin-to-beta-globin switching, which causes high levels of fetal hemoglobin expression throughout the patients’ lives.
So the researchers set out to mimic this phenomenon in HSPCs from patients with SCD.
The team performed CRISPR–Cas9-mediated genome editing of the HSPCs to mutate a 13-nt sequence present in the promoters of the HBG1 and HBG2 genes.
In this way, they were able to recapitulate a naturally occurring HPFH-associated mutation, so the HSPCs produced RBCs with increased fetal hemoglobin levels.
“Our work has identified a potential DNA target for genome-editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia,” Dr Weiss said.
“We have been able to snip that DNA target using CRISPR, remove a short segment in a ‘control section’ of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells.”
Recently, scientists have used several genome-editing approaches to manipulate HSPCs for the possible treatment of SCD and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching.
“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system,” Dr Weiss said.
He and his colleagues noted that, at this stage, it is still too early to begin clinical trials of their approach. The researchers want to refine the genome-editing process and perform other experiments to minimize potentially harmful off-target mutations before clinical trials are considered.
In addition, they said it will be important to compare the different genome-editing approaches head-to-head to determine which is safest and most effective.
and a sickled one
Image by Betty Pace
CRISPR-Cas9-mediated genome editing might be a feasible approach for treating sickle cell disease (SCD), according to a group of researchers.
The team used CRISPR to edit hematopoietic stem and progenitor cells (HSPCs) from patients with SCD, which resulted in the production of red blood cells (RBCs) that had enough fetal hemoglobin to be healthy.
The researchers believe this approach might prove effective in treating beta-thalassemia as well.
“Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin,” said study author Mitchell J. Weiss, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia . . . . We have found a way to use CRISPR gene editing to produce similar benefits.”
Dr Weiss and his colleagues described this method in Nature Medicine.
The researchers noted that SCD and beta-thalassemia become symptomatic when fetal gamma-globin expression from 2 genes, HBG1 and HBG2, decreases and the expression of adult beta-globin increases, which shifts RBC hemoglobin from the fetal form to the adult form.
Reversing this shift can raise levels of fetal hemoglobin and ameliorate the symptoms of beta-thalassemia or SCD.
The team also pointed out that, in people with a benign genetic condition known as hereditary persistence of fetal hemoglobin (HPFH), mutations attenuate gamma-globin-to-beta-globin switching, which causes high levels of fetal hemoglobin expression throughout the patients’ lives.
So the researchers set out to mimic this phenomenon in HSPCs from patients with SCD.
The team performed CRISPR–Cas9-mediated genome editing of the HSPCs to mutate a 13-nt sequence present in the promoters of the HBG1 and HBG2 genes.
In this way, they were able to recapitulate a naturally occurring HPFH-associated mutation, so the HSPCs produced RBCs with increased fetal hemoglobin levels.
“Our work has identified a potential DNA target for genome-editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia,” Dr Weiss said.
“We have been able to snip that DNA target using CRISPR, remove a short segment in a ‘control section’ of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells.”
Recently, scientists have used several genome-editing approaches to manipulate HSPCs for the possible treatment of SCD and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching.
“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system,” Dr Weiss said.
He and his colleagues noted that, at this stage, it is still too early to begin clinical trials of their approach. The researchers want to refine the genome-editing process and perform other experiments to minimize potentially harmful off-target mutations before clinical trials are considered.
In addition, they said it will be important to compare the different genome-editing approaches head-to-head to determine which is safest and most effective.
and a sickled one
Image by Betty Pace
CRISPR-Cas9-mediated genome editing might be a feasible approach for treating sickle cell disease (SCD), according to a group of researchers.
The team used CRISPR to edit hematopoietic stem and progenitor cells (HSPCs) from patients with SCD, which resulted in the production of red blood cells (RBCs) that had enough fetal hemoglobin to be healthy.
The researchers believe this approach might prove effective in treating beta-thalassemia as well.
“Our approach to gene editing is informed by the known benefits of hereditary persistence of fetal hemoglobin,” said study author Mitchell J. Weiss, MD, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“It has been known for some time that individuals with genetic mutations that persistently elevate fetal hemoglobin are resistant to the symptoms of sickle cell disease and beta-thalassemia . . . . We have found a way to use CRISPR gene editing to produce similar benefits.”
Dr Weiss and his colleagues described this method in Nature Medicine.
The researchers noted that SCD and beta-thalassemia become symptomatic when fetal gamma-globin expression from 2 genes, HBG1 and HBG2, decreases and the expression of adult beta-globin increases, which shifts RBC hemoglobin from the fetal form to the adult form.
Reversing this shift can raise levels of fetal hemoglobin and ameliorate the symptoms of beta-thalassemia or SCD.
The team also pointed out that, in people with a benign genetic condition known as hereditary persistence of fetal hemoglobin (HPFH), mutations attenuate gamma-globin-to-beta-globin switching, which causes high levels of fetal hemoglobin expression throughout the patients’ lives.
So the researchers set out to mimic this phenomenon in HSPCs from patients with SCD.
The team performed CRISPR–Cas9-mediated genome editing of the HSPCs to mutate a 13-nt sequence present in the promoters of the HBG1 and HBG2 genes.
In this way, they were able to recapitulate a naturally occurring HPFH-associated mutation, so the HSPCs produced RBCs with increased fetal hemoglobin levels.
“Our work has identified a potential DNA target for genome-editing-mediated therapy and offers proof-of-principle for a possible approach to treat sickle cell and beta-thalassemia,” Dr Weiss said.
“We have been able to snip that DNA target using CRISPR, remove a short segment in a ‘control section’ of DNA that stimulates gamma-to-beta switching, and join the ends back up to produce sustained elevation of fetal hemoglobin levels in adult red blood cells.”
Recently, scientists have used several genome-editing approaches to manipulate HSPCs for the possible treatment of SCD and beta-thalassemia, including repair of specific disease-causing mutations and other strategies to inhibit gamma-to-beta switching.
“Our results represent an additional approach to these existing innovative strategies and compare favorably in terms of the levels of fetal hemoglobin that are produced by our experimental system,” Dr Weiss said.
He and his colleagues noted that, at this stage, it is still too early to begin clinical trials of their approach. The researchers want to refine the genome-editing process and perform other experiments to minimize potentially harmful off-target mutations before clinical trials are considered.
In addition, they said it will be important to compare the different genome-editing approaches head-to-head to determine which is safest and most effective.
Drivers of cardiac complications in sickle cell anemia
with sickle cell anemia
Image courtesy of the
University of Michigan
Preclinical research has revealed malfunctioning molecular pathways associated with cardiac anomalies in sickle cell anemia (SCA) that lead to sudden death.
Researchers used a mouse model of SCA and identified a unique “restrictive cardiomyopathy” that is superimposed on the anemia-associated heart enlargement.
They also found upregulated gene expression that fuels myocardial fibrosis and electrophysiological changes.
The researchers believe these findings, published in PNAS, will aid the development of new targeted therapies to treat cardiac dysfunction in patients with SCA.
“Sickle cell anemia is associated with significant morbidity and mortality, including a high incidence of unexplained, sudden death in young adults,” said study author Punam Malik, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“Our findings may provide a unifying cardiac pathophysiology that explains reported cardiac abnormalities and sudden death seen in humans with SCA.”
To find pathologies specific to SCA, Dr Malik and his colleagues compared mice bred to have SCA and wild-type mice with experimentally induced chronic anemia.
The mice underwent serial comprehensive cardiac analysis, including detailed cardiac imaging (MRI), electrocardiography, and microscopic cross-section analysis of heart tissues (histopathology and electron microscopy).
The researchers said that, in the SCA mice, they observed a distinctive sickle cardiomyopathy in which restrictive physiology was superimposed on chronic anemia and predisposed the mice to sudden death.
The SCA mice had progressive left atrial enlargement and diastolic dysfunction but preserved systolic function. This restrictive physiology appeared to be caused by ischemic-scattered cardiomyocyte loss, myocardial fibrosis, and cardiac remodeling.
The researchers also conducted transcriptome analysis. This revealed that SCA mice had upregulation of genes that cause increased oxidation, hypoxia, and fibrosis in heart tissues. It also showed a downregulation of genes associated with electrophysiological function.
Finally, the team observed progressive corrected QT prolongation, arrhythmias, and ischemic changes in the SCA mice shortly before a significant number of the animals experienced sudden death.
The researchers are continuing to study the molecular mechanisms and pathways that trigger myocardial fibrosis in SCA, using a variety of knockout mice.
In addition, the successful use of noninvasive cardiac imaging techniques in this study inspired the researchers to launch a clinical trial to test these early diagnostic techniques on people with SCA. Enrollment in that study is now complete.
“It is incredibly exciting to see that this work has inspired clinical trials and other research studies,” said study author Nihal Bakeer, MD, of the Indiana Hemophilia and Thrombosis Center in Indianapolis.
“Our goal has always been [to] find the underling pathobiology of cardiac complications in sickle cell anemia and help find new diagnostics and therapeutics to decrease the morbidity and rate of sudden cardiac death in young adults with SCA.”
with sickle cell anemia
Image courtesy of the
University of Michigan
Preclinical research has revealed malfunctioning molecular pathways associated with cardiac anomalies in sickle cell anemia (SCA) that lead to sudden death.
Researchers used a mouse model of SCA and identified a unique “restrictive cardiomyopathy” that is superimposed on the anemia-associated heart enlargement.
They also found upregulated gene expression that fuels myocardial fibrosis and electrophysiological changes.
The researchers believe these findings, published in PNAS, will aid the development of new targeted therapies to treat cardiac dysfunction in patients with SCA.
“Sickle cell anemia is associated with significant morbidity and mortality, including a high incidence of unexplained, sudden death in young adults,” said study author Punam Malik, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“Our findings may provide a unifying cardiac pathophysiology that explains reported cardiac abnormalities and sudden death seen in humans with SCA.”
To find pathologies specific to SCA, Dr Malik and his colleagues compared mice bred to have SCA and wild-type mice with experimentally induced chronic anemia.
The mice underwent serial comprehensive cardiac analysis, including detailed cardiac imaging (MRI), electrocardiography, and microscopic cross-section analysis of heart tissues (histopathology and electron microscopy).
The researchers said that, in the SCA mice, they observed a distinctive sickle cardiomyopathy in which restrictive physiology was superimposed on chronic anemia and predisposed the mice to sudden death.
The SCA mice had progressive left atrial enlargement and diastolic dysfunction but preserved systolic function. This restrictive physiology appeared to be caused by ischemic-scattered cardiomyocyte loss, myocardial fibrosis, and cardiac remodeling.
The researchers also conducted transcriptome analysis. This revealed that SCA mice had upregulation of genes that cause increased oxidation, hypoxia, and fibrosis in heart tissues. It also showed a downregulation of genes associated with electrophysiological function.
Finally, the team observed progressive corrected QT prolongation, arrhythmias, and ischemic changes in the SCA mice shortly before a significant number of the animals experienced sudden death.
The researchers are continuing to study the molecular mechanisms and pathways that trigger myocardial fibrosis in SCA, using a variety of knockout mice.
In addition, the successful use of noninvasive cardiac imaging techniques in this study inspired the researchers to launch a clinical trial to test these early diagnostic techniques on people with SCA. Enrollment in that study is now complete.
“It is incredibly exciting to see that this work has inspired clinical trials and other research studies,” said study author Nihal Bakeer, MD, of the Indiana Hemophilia and Thrombosis Center in Indianapolis.
“Our goal has always been [to] find the underling pathobiology of cardiac complications in sickle cell anemia and help find new diagnostics and therapeutics to decrease the morbidity and rate of sudden cardiac death in young adults with SCA.”
with sickle cell anemia
Image courtesy of the
University of Michigan
Preclinical research has revealed malfunctioning molecular pathways associated with cardiac anomalies in sickle cell anemia (SCA) that lead to sudden death.
Researchers used a mouse model of SCA and identified a unique “restrictive cardiomyopathy” that is superimposed on the anemia-associated heart enlargement.
They also found upregulated gene expression that fuels myocardial fibrosis and electrophysiological changes.
The researchers believe these findings, published in PNAS, will aid the development of new targeted therapies to treat cardiac dysfunction in patients with SCA.
“Sickle cell anemia is associated with significant morbidity and mortality, including a high incidence of unexplained, sudden death in young adults,” said study author Punam Malik, MD, of Cincinnati Children’s Hospital Medical Center in Ohio.
“Our findings may provide a unifying cardiac pathophysiology that explains reported cardiac abnormalities and sudden death seen in humans with SCA.”
To find pathologies specific to SCA, Dr Malik and his colleagues compared mice bred to have SCA and wild-type mice with experimentally induced chronic anemia.
The mice underwent serial comprehensive cardiac analysis, including detailed cardiac imaging (MRI), electrocardiography, and microscopic cross-section analysis of heart tissues (histopathology and electron microscopy).
The researchers said that, in the SCA mice, they observed a distinctive sickle cardiomyopathy in which restrictive physiology was superimposed on chronic anemia and predisposed the mice to sudden death.
The SCA mice had progressive left atrial enlargement and diastolic dysfunction but preserved systolic function. This restrictive physiology appeared to be caused by ischemic-scattered cardiomyocyte loss, myocardial fibrosis, and cardiac remodeling.
The researchers also conducted transcriptome analysis. This revealed that SCA mice had upregulation of genes that cause increased oxidation, hypoxia, and fibrosis in heart tissues. It also showed a downregulation of genes associated with electrophysiological function.
Finally, the team observed progressive corrected QT prolongation, arrhythmias, and ischemic changes in the SCA mice shortly before a significant number of the animals experienced sudden death.
The researchers are continuing to study the molecular mechanisms and pathways that trigger myocardial fibrosis in SCA, using a variety of knockout mice.
In addition, the successful use of noninvasive cardiac imaging techniques in this study inspired the researchers to launch a clinical trial to test these early diagnostic techniques on people with SCA. Enrollment in that study is now complete.
“It is incredibly exciting to see that this work has inspired clinical trials and other research studies,” said study author Nihal Bakeer, MD, of the Indiana Hemophilia and Thrombosis Center in Indianapolis.
“Our goal has always been [to] find the underling pathobiology of cardiac complications in sickle cell anemia and help find new diagnostics and therapeutics to decrease the morbidity and rate of sudden cardiac death in young adults with SCA.”
How hydroxyurea fights sickle cell disease
Photo by Zak Hubbard
Researchers say they have uncovered hydroxyurea’s main mechanism of action in sickle cell disease (SCD).
The drug’s mechanism has been a topic of debate, with some researchers claiming hydroxyurea works by reactivating fetal hemoglobin and others saying it increases the volume of red blood cells (RBCs), thereby reducing the concentration of sickle hemoglobin.
Now, research published in PNAS suggests the latter mechanism is the dominant one.
“Our findings shine a light on the mechanism behind hydroxyurea action, which has long been debated in the scientific community,” said study author Ming Dao, PhD, of the Massachusetts Institute of Technology in Cambridge.
“It’s exciting to see that, using the latest optical imaging tools, we can now confirm which one is the dominating mechanism. Understanding the key mechanism of action will allow us to explore novel and improved therapeutic approaches for sickle cell disease.”
For this study, the researchers analyzed blood samples from patients with SCD.
The team used common-path interferometric microscopy to assess the biophysical properties (shape, surface area, and volume) and biomechanical properties (flexibility and stickiness) of RBCs.
The researchers separated RBCs into 4 groups based on their density. Normal, disc-shaped cells were the least dense, while severely sickled cells were the densest.
The team then compares samples from patients who were taking hydroxyurea and those who were not.
The RBCs of patients receiving treatment showed an improvement in all of the biophysical and biomechanical properties tested across all density levels.
Improvement in the physical properties of RBCs from patients treated with hydroxyurea correlated more with an increase in RBC volume than with levels of fetal hemoglobin.
The researchers hope these biophysical markers can be combined with biochemical and molecular-level markers to assess the severity of a patient’s disease, determine whether or not a patient will respond to hydroxyurea, and monitor the effectiveness of that treatment.
“There is a critical need for patient-specific biomarkers that can be used to assess the effectiveness of treatments for sickle cell disease,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.
“This study shows how techniques commonly used in engineering and physics can help us to better understand how the red blood cells in people with sickle cell disease react to treatment, which could lead to improved diagnostics and therapies.”
Photo by Zak Hubbard
Researchers say they have uncovered hydroxyurea’s main mechanism of action in sickle cell disease (SCD).
The drug’s mechanism has been a topic of debate, with some researchers claiming hydroxyurea works by reactivating fetal hemoglobin and others saying it increases the volume of red blood cells (RBCs), thereby reducing the concentration of sickle hemoglobin.
Now, research published in PNAS suggests the latter mechanism is the dominant one.
“Our findings shine a light on the mechanism behind hydroxyurea action, which has long been debated in the scientific community,” said study author Ming Dao, PhD, of the Massachusetts Institute of Technology in Cambridge.
“It’s exciting to see that, using the latest optical imaging tools, we can now confirm which one is the dominating mechanism. Understanding the key mechanism of action will allow us to explore novel and improved therapeutic approaches for sickle cell disease.”
For this study, the researchers analyzed blood samples from patients with SCD.
The team used common-path interferometric microscopy to assess the biophysical properties (shape, surface area, and volume) and biomechanical properties (flexibility and stickiness) of RBCs.
The researchers separated RBCs into 4 groups based on their density. Normal, disc-shaped cells were the least dense, while severely sickled cells were the densest.
The team then compares samples from patients who were taking hydroxyurea and those who were not.
The RBCs of patients receiving treatment showed an improvement in all of the biophysical and biomechanical properties tested across all density levels.
Improvement in the physical properties of RBCs from patients treated with hydroxyurea correlated more with an increase in RBC volume than with levels of fetal hemoglobin.
The researchers hope these biophysical markers can be combined with biochemical and molecular-level markers to assess the severity of a patient’s disease, determine whether or not a patient will respond to hydroxyurea, and monitor the effectiveness of that treatment.
“There is a critical need for patient-specific biomarkers that can be used to assess the effectiveness of treatments for sickle cell disease,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.
“This study shows how techniques commonly used in engineering and physics can help us to better understand how the red blood cells in people with sickle cell disease react to treatment, which could lead to improved diagnostics and therapies.”
Photo by Zak Hubbard
Researchers say they have uncovered hydroxyurea’s main mechanism of action in sickle cell disease (SCD).
The drug’s mechanism has been a topic of debate, with some researchers claiming hydroxyurea works by reactivating fetal hemoglobin and others saying it increases the volume of red blood cells (RBCs), thereby reducing the concentration of sickle hemoglobin.
Now, research published in PNAS suggests the latter mechanism is the dominant one.
“Our findings shine a light on the mechanism behind hydroxyurea action, which has long been debated in the scientific community,” said study author Ming Dao, PhD, of the Massachusetts Institute of Technology in Cambridge.
“It’s exciting to see that, using the latest optical imaging tools, we can now confirm which one is the dominating mechanism. Understanding the key mechanism of action will allow us to explore novel and improved therapeutic approaches for sickle cell disease.”
For this study, the researchers analyzed blood samples from patients with SCD.
The team used common-path interferometric microscopy to assess the biophysical properties (shape, surface area, and volume) and biomechanical properties (flexibility and stickiness) of RBCs.
The researchers separated RBCs into 4 groups based on their density. Normal, disc-shaped cells were the least dense, while severely sickled cells were the densest.
The team then compares samples from patients who were taking hydroxyurea and those who were not.
The RBCs of patients receiving treatment showed an improvement in all of the biophysical and biomechanical properties tested across all density levels.
Improvement in the physical properties of RBCs from patients treated with hydroxyurea correlated more with an increase in RBC volume than with levels of fetal hemoglobin.
The researchers hope these biophysical markers can be combined with biochemical and molecular-level markers to assess the severity of a patient’s disease, determine whether or not a patient will respond to hydroxyurea, and monitor the effectiveness of that treatment.
“There is a critical need for patient-specific biomarkers that can be used to assess the effectiveness of treatments for sickle cell disease,” said study author Subra Suresh, ScD, of Carnegie Mellon University in Pittsburgh, Pennsylvania.
“This study shows how techniques commonly used in engineering and physics can help us to better understand how the red blood cells in people with sickle cell disease react to treatment, which could lead to improved diagnostics and therapies.”
Teva launches generic imatinib tablets in US
Photo by Steven Harbour
Teva Pharmaceutical Industries Ltd. has announced the US launch of imatinib mesylate, the generic equivalent of Novartis’s Gleevec®, in 100 mg and 400 mg tablets.
In the US, imatinib is approved to treat newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase, blast crisis, and accelerated phase, as well as Ph+
chronic myeloid leukemia in chronic phase after failure of interferon-alpha therapy.
Imatinib is also approved to treat adults with relapsed or refractory Ph+ acute lymphoblastic leukemia, adults with myelodysplastic syndromes or myeloproliferative neoplasms associated with platelet-derived growth factor receptor gene re-arrangements, and adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status.
In addition, imatinib is approved to treat adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (regardless of whether they have the FIP1L1-PDGFRα fusion kinase) and adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.
Finally, the drug is approved as an adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors in adults.
For more details on imatinib, see the full prescribing information.
Photo by Steven Harbour
Teva Pharmaceutical Industries Ltd. has announced the US launch of imatinib mesylate, the generic equivalent of Novartis’s Gleevec®, in 100 mg and 400 mg tablets.
In the US, imatinib is approved to treat newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase, blast crisis, and accelerated phase, as well as Ph+
chronic myeloid leukemia in chronic phase after failure of interferon-alpha therapy.
Imatinib is also approved to treat adults with relapsed or refractory Ph+ acute lymphoblastic leukemia, adults with myelodysplastic syndromes or myeloproliferative neoplasms associated with platelet-derived growth factor receptor gene re-arrangements, and adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status.
In addition, imatinib is approved to treat adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (regardless of whether they have the FIP1L1-PDGFRα fusion kinase) and adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.
Finally, the drug is approved as an adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors in adults.
For more details on imatinib, see the full prescribing information.
Photo by Steven Harbour
Teva Pharmaceutical Industries Ltd. has announced the US launch of imatinib mesylate, the generic equivalent of Novartis’s Gleevec®, in 100 mg and 400 mg tablets.
In the US, imatinib is approved to treat newly diagnosed Philadelphia-chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase, blast crisis, and accelerated phase, as well as Ph+
chronic myeloid leukemia in chronic phase after failure of interferon-alpha therapy.
Imatinib is also approved to treat adults with relapsed or refractory Ph+ acute lymphoblastic leukemia, adults with myelodysplastic syndromes or myeloproliferative neoplasms associated with platelet-derived growth factor receptor gene re-arrangements, and adults with aggressive systemic mastocytosis without the D816V c-Kit mutation or with unknown c-Kit mutational status.
In addition, imatinib is approved to treat adults with hypereosinophilic syndrome and/or chronic eosinophilic leukemia (regardless of whether they have the FIP1L1-PDGFRα fusion kinase) and adults with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.
Finally, the drug is approved as an adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors in adults.
For more details on imatinib, see the full prescribing information.
Products granted orphan designation for use in HSCT
The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.
Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).
Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.
If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.
About orphan designation
Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.
In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.
BPX-501/rimiducid development
BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.
The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.
These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.
Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.
The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.
BP-004 trial
BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.
One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.
The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.”
The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.
Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).
Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.
If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.
About orphan designation
Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.
In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.
BPX-501/rimiducid development
BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.
The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.
These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.
Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.
The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.
BP-004 trial
BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.
One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.
The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.”
The European Commission has granted orphan drug designation for the T-cell therapy product candidate BPX-501 and the small molecule rimiducid.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity.
Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
The goal of this therapy is to allow physicians to more safely perform haploidentical hematopoietic stem cell transplant (haplo-HSCT).
Haplo-HSCT recipients receive BPX-501 to speed immune reconstitution and provide control over viral infections. And rimiducid is used to eliminate BPX-501 alloreactive T cells if severe graft-vs-host disease (GVHD) occurs.
If a patient develops severe GVHD, rimiducid is used to trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.
About orphan designation
Orphan drug designation from the European Commission provides regulatory and financial incentives for companies to develop and market therapies that treat serious or life-threatening conditions that affect no more than 5 in 10,000 people in the European Union (EU), and where no treatment is currently approved.
In addition to a 10-year period of marketing exclusivity in the EU upon product approval, orphan drug designation provides fee waivers, protocol assistance, and marketing authorization under the centralized procedure granting approval in all EU countries.
BPX-501/rimiducid development
BPX-501 and rimiducid are being developed by Bellicum Pharmaceuticals.
The company has met with regulatory authorities in Europe to discuss the potential approval pathway for BPX-501 and rimiducid for the treatment of immunodeficiency and GVHD following haplo-HSCT in pediatric patients with leukemias, lymphomas, and rare inherited blood diseases who do not have a matched donor.
These discussions have resulted in an initial agreement regarding the company’s development plans, subject to further refinement in a formal protocol assistance process that is available for orphan drug products.
Based on regulatory discussions, Bellicum believes that data from the European arm of its BP-004 trial, with a 6-month follow-up time and expanded to enroll additional patients, could form the basis of marketing authorization applications for BPX-501 and rimiducid.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has agreed that review and approval under “exceptional circumstances” may be suitable, recognizing that a randomized trial may not be feasible in the pediatric setting. In place of a randomized trial, Bellicum intends to collect data from a concurrent observational study of allogeneic HSCT outcomes in the pediatric setting.
The European Medicines Agency can grant early market authorization to orphan drug products under exceptional circumstances. Exceptional circumstances can be granted for medicines that treat very rare diseases or where controlled studies are impractical or not consistent with accepted principles of medical ethics.
BP-004 trial
BP-004 is a phase 1/2 dose-escalation trial of BPX-501 and rimiducid in pediatric patients with malignant and nonmalignant diseases. Interim results from this trial were reported in 2 presentations at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation in April 2016.
One presentation involved patients with acute leukemia who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free. There were several cases of GVHD, but nearly all were resolved.
The other presentation covered patients with nonmalignant disorders who received BPX-501 after haplo-HSCT. At a median follow-up of 7 months, all 24 patients studied were still alive and disease-free. The incidence of GVHD was considered “very low.”