Gene Therapy

ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.

Andrew D. Bowser/MDedge News

Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.

BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.

The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.

“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.

“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.

The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.

Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.

Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.

“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.

ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.

Andrew D. Bowser/MDedge News

Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.

BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.

The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.

“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.

“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.

The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.

Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.

Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.

“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.

ORLANDO – A gene therapy approach that targets a major repressor of fetal hemoglobin appears to be acceptably safe and to mitigate the pathology of sickle cell disease among the five patients infused so far, an investigator reported at the annual meeting of the American Society of Hematology.

Andrew D. Bowser/MDedge News

Knocking down BCL11A using a lentiviral vector-based approach resulted in effective induction of fetal hemoglobin and significant attenuation of the sickling phenotype, with no vector-related adverse events, investigator Erica B. Esrick, MD, of Children’s Hospital Boston, said during the meeting’s late-breaking abstracts session.

The single-center pilot and feasibility study, originally designed to include a total of seven patients, now has an expanded enrollment goal of 15 patients, and a multicenter phase 2/3 study is planned that will enroll a larger group of patients with sickle cell disease, according to Dr. Esrick.

BCL11A represents a promising target in sickle cell disease because of its regulation of the fetal-adult hemoglobin switch at the gamma-globin locus, investigators said in their late-breaking study abstract.

Dr. Esrick described BCH-BB694, a lentiviral vector encoding a BCL11A-targeting small hairpin RNA embedded in a microRNA scaffold (shmiR). “The advantage of this approach is that it harnesses the physiologic switch machinery, simultaneously increasing fetal hemoglobin and decreasing sickle hemoglobin, thus maintaining the alpha to beta globin ratio in the cell,” she said.

The results of the pilot study of the shmiR vector approach, although preliminary and in need of longer follow-up, contribute to a larger body of research showing that multiple gene therapy approaches hold promise in this disease, said Robert Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine, Baltimore.

“The exciting thing is that there are now multiple ways of going at this previously incurable disease,” Dr. Brodsky, who was not involved in the research, said during a press conference.

Development of the gene therapy described by Dr. Esrick involves mobilization of the patient’s peripheral stem cells using plerixafor, followed by selection of CD34+ cells that were transduced with the shmiR lentiviral vector, followed by infusion of gene modified cells into the patient after a busulfan conditioning regimen.

“In our treated patients, we’ve seen a consistent and substantial induction in fetal hemoglobin,” Dr. Esrick said, noting that the longest follow-up to date for the five treated patients is now 18 months.

The patients, who range in age from 12 to 26 years, are producing and maintaining very high numbers of F cells, or erythrocytes with measurable fetal hemoglobin, she said.

Total fetal hemoglobin has increased and remained stable at between 23% and 43% for the five patients, who are producing “stably high” average amounts of fetal hemoglobin per F cell, at 10 to 16 picograms of fetal hemoglobin per cell, while 37% to 62% of the F cells’ total hemoglobin is fetal hemoglobin, she added.

Following gene therapy, treated patients have had no instances of vaso-occlusive pain crises, respiratory events, or neurologic events. No patients have required transfusion, except one with severe underlying vascular disease for whom post–gene therapy transfusions were planned, she said.

Validated assays at the single-cell level are needed to better understand the effect of this gene therapy and eventually compare it to other therapeutic approaches in sickle cell disease, according to Dr. Esrick.

“We’re collaborating with several colleagues on exploratory assays to accomplish this,” she said, adding that the work is ongoing.

Dr. Esrick reported having no disclosures. Her coauthors reported disclosures related to Alerion Biosciences, Novartis, Orchard Therapeutics, Roche, AstraZeneca, and bluebird bio, among others.

SOURCE: Esrick EB et al. ASH 2019. Abstract LBA-5.

WASHINGTON– Gene therapy for the treatment of rare diseases continues to develop and new products are entering the pipeline; however, more work is needed to make the gene therapy experience easier on patients and their families, according to members of a panel at the NORD Rare Diseases & Orphan Product Breakthrough Summit, held by the National Organization for Rare Disorders.

Companies developing gene therapy cite their main challenges as identifying patients, developing clinical trials, coordinating treatment and supporting families, managing reimbursement, and manufacturing the treatment, said Mark Rothera, president and CEO of Orchard Therapeutics, developer of ex vivo autologous hematopoietic stem cell gene therapy.

For families of patients with rare diseases who are undergoing gene therapy, challenges include struggles such as language barriers, lack of wifi, and separation from other family members for extended periods, according to Amy Price, mother of a gene therapy recipient, as well as principal consultant to Rarallel and an advocate for metachromatic leukodystrophy.

Ms. Price cited a survey she conducted of families with children who underwent gene therapy. She collected data from 16 families about their initial visit as part of a gene therapy trial; the trials included 14 families in Milan; 1 in Bethesda, Md.; and 1 in Paris. The average age of the patients at the start of the trial was 3 years, with a range of 8 months to 11 years. The trials were conducted between 1990 and 2018.

Families participating in the trials spent an average of 5.5 months in the city where the trial was conducted, and an average of 48 days in an isolation ward with their child at the start of the study.

The five biggest challenges were financial well-being (cited by 60% of survey respondents), social isolation/being away from support system (60%), fear of the unknown/long-term treatment diagnosis (73%), family separation (67%), and caring for other children simultaneous during the trial period (60%).

In addition, patients averaged 12 follow-up visits, and the most common secondary challenges cited in the survey included time spent at the hospital, emotional and physical stress on the patient, fear of test results and outcomes, exhaustion, time away from work and school, and travel logistics.

Other stressors include language barriers and not being in children’s hospital, Ms. Price said.

Ms. Price proposed patient-focused solutions such as addressing cultural challenges, connecting families to local resources, and providing clinical follow-up locally to reduce the burden of travel to the trial site.

WASHINGTON– Gene therapy for the treatment of rare diseases continues to develop and new products are entering the pipeline; however, more work is needed to make the gene therapy experience easier on patients and their families, according to members of a panel at the NORD Rare Diseases & Orphan Product Breakthrough Summit, held by the National Organization for Rare Disorders.

Companies developing gene therapy cite their main challenges as identifying patients, developing clinical trials, coordinating treatment and supporting families, managing reimbursement, and manufacturing the treatment, said Mark Rothera, president and CEO of Orchard Therapeutics, developer of ex vivo autologous hematopoietic stem cell gene therapy.

For families of patients with rare diseases who are undergoing gene therapy, challenges include struggles such as language barriers, lack of wifi, and separation from other family members for extended periods, according to Amy Price, mother of a gene therapy recipient, as well as principal consultant to Rarallel and an advocate for metachromatic leukodystrophy.

Ms. Price cited a survey she conducted of families with children who underwent gene therapy. She collected data from 16 families about their initial visit as part of a gene therapy trial; the trials included 14 families in Milan; 1 in Bethesda, Md.; and 1 in Paris. The average age of the patients at the start of the trial was 3 years, with a range of 8 months to 11 years. The trials were conducted between 1990 and 2018.

Families participating in the trials spent an average of 5.5 months in the city where the trial was conducted, and an average of 48 days in an isolation ward with their child at the start of the study.

The five biggest challenges were financial well-being (cited by 60% of survey respondents), social isolation/being away from support system (60%), fear of the unknown/long-term treatment diagnosis (73%), family separation (67%), and caring for other children simultaneous during the trial period (60%).

In addition, patients averaged 12 follow-up visits, and the most common secondary challenges cited in the survey included time spent at the hospital, emotional and physical stress on the patient, fear of test results and outcomes, exhaustion, time away from work and school, and travel logistics.

Other stressors include language barriers and not being in children’s hospital, Ms. Price said.

Ms. Price proposed patient-focused solutions such as addressing cultural challenges, connecting families to local resources, and providing clinical follow-up locally to reduce the burden of travel to the trial site.

WASHINGTON– Gene therapy for the treatment of rare diseases continues to develop and new products are entering the pipeline; however, more work is needed to make the gene therapy experience easier on patients and their families, according to members of a panel at the NORD Rare Diseases & Orphan Product Breakthrough Summit, held by the National Organization for Rare Disorders.

Companies developing gene therapy cite their main challenges as identifying patients, developing clinical trials, coordinating treatment and supporting families, managing reimbursement, and manufacturing the treatment, said Mark Rothera, president and CEO of Orchard Therapeutics, developer of ex vivo autologous hematopoietic stem cell gene therapy.

For families of patients with rare diseases who are undergoing gene therapy, challenges include struggles such as language barriers, lack of wifi, and separation from other family members for extended periods, according to Amy Price, mother of a gene therapy recipient, as well as principal consultant to Rarallel and an advocate for metachromatic leukodystrophy.

Ms. Price cited a survey she conducted of families with children who underwent gene therapy. She collected data from 16 families about their initial visit as part of a gene therapy trial; the trials included 14 families in Milan; 1 in Bethesda, Md.; and 1 in Paris. The average age of the patients at the start of the trial was 3 years, with a range of 8 months to 11 years. The trials were conducted between 1990 and 2018.

Families participating in the trials spent an average of 5.5 months in the city where the trial was conducted, and an average of 48 days in an isolation ward with their child at the start of the study.

The five biggest challenges were financial well-being (cited by 60% of survey respondents), social isolation/being away from support system (60%), fear of the unknown/long-term treatment diagnosis (73%), family separation (67%), and caring for other children simultaneous during the trial period (60%).

In addition, patients averaged 12 follow-up visits, and the most common secondary challenges cited in the survey included time spent at the hospital, emotional and physical stress on the patient, fear of test results and outcomes, exhaustion, time away from work and school, and travel logistics.

Other stressors include language barriers and not being in children’s hospital, Ms. Price said.

Ms. Price proposed patient-focused solutions such as addressing cultural challenges, connecting families to local resources, and providing clinical follow-up locally to reduce the burden of travel to the trial site.

Early results indicate experimental gene therapies could illicit a cure for sickle cell disease (SCD), but many barriers to access remain, namely cost, experts reported during a recent webinar sponsored by the National Heart, Lung, and Blood Institute.

Pogonic/Getty Images

At present, allogeneic hematopoietic stem cell transplant remains the only curative therapy available for patients with SCD. Newer transplant techniques include the use of mobilized blood stem cells, where stem cells are collected from the circulation using blood cell growth factors, explained Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

The most promising experimental gene therapies currently undergoing clinical development are gene-addition and gene-editing therapies, he said. Another technique, in vivo gene editing to correct the sickle mutation, is also being investigated, but has not yet reached clinical development.
 

Gene-addition therapy

Gene-addition therapy is a technique where a fetal hemoglobin (HbF) or anti-sickling beta-hemoglobin gene is inserted into a hematopoietic stem cell to illicit a curative effect. In this technique, the corrective gene is harvested from a patient’s own blood stem cells.

In patients with SCD, when HbF levels are elevated, the likelihood of sickling is reduced, resulting in a milder form of disease. As a result, raising HbF levels is a therapeutic target that forms the basis of several ongoing clinical studies.

The technique involves packaging an HbF rescue gene into a viral vector and coincubating the vector with a patient’s own blood stem cells. Subsequently, the corrected stem cells are injected back into the patient to produce higher levels of HbF.

The ongoing phase 1/2 HGB-206 clinical study is evaluating this technique in patients aged 12-50 years with severe SCD in multiple centers throughout Europe and the United States.

In those treated thus far, initial results appear promising, Dr. Walters reported, with one patient experiencing a rise in Hb levels from 10.7 g/dL at 3 months to 15.0 g/dL at 15 months follow-up.

Dr. Walters also reported that some of these patients no longer exhibit any signs or symptoms of SCD, such as anemia or painful adverse events. While these initial findings are compelling, whether these benefits will be maintained is still unknown.

“While it’s too early to call this a cure, if [these results] could be extended for 5, 10, or 15 years, I think everyone would agree that this would be a cure,” he said.

This technique could be universally available, he said, since a patient’s own blood stem cells are used. Other complications, such as graft-versus-host disease (GVHD) or immune-related reactions, are negated with this form of therapy, he said.

Recent evidence has demonstrated that only about 20% of donor stem cells need to be corrected to illicit a very strong effect. This principle is now being applied in gene-editing techniques, as correcting every gene in every stem cell would be very challenging, Dr. Walters explained.
 

Gene editing

Another technique being investigated in SCD is gene editing, in which the fetal hemoglobin gene is “reawakened,” or other techniques are used to correct the sickle gene directly, such as CRISPR-Cas9 technology, Dr. Walters said.

In this technique, the Cas9 protein makes a cut and repairs an individual’s genomic DNA by inserting a strand of corrected donor DNA. The novel technology would allow for targeted genome editing that is specific to the SCD patient.

Currently, this experimental therapy is being investigated in preclinical studies. Dr. Walters said that he and his colleagues hope to begin enrolling patients in clinical trials within the next 1-2 years.

But while some gene therapies have been approved in other disorders, such as spinal muscle atrophy, a limiting factor to widespread availability is cost. Despite promising initial results in SCD, the affordability of future gene therapies will be a key factor to universal access, Dr. Walters said.
 

The Cure Sickle Cell Initiative

Traci Mondoro, PhD, chief of the Translational Blood Science and Resources Branch at NHLBI, explained that the NHLBI has funded a large proportion of the research that has formed the basis of several genetically based clinical studies.

One of the primary goals of the Cure Sickle Cell Initiative is to bridge the gap between new research and the SCD community. Their aim is to improve access for patients to participate in genetically based studies to advance cures.

The comprehensive approach is intended to fill in existing gaps by funding breakthrough research in both academic and private settings.

By establishing partnerships with key stakeholders, institutions, and patient groups, Dr. Mondoro said they hope to increase patient participation in clinical trials involving curative therapies. In the future, they also intend to establish a large body of evidence to provide adequate safety data to study these therapies in pediatric populations.

Dr. Walters and Dr. Mondoro did not provide information on financial disclosures.

Early results indicate experimental gene therapies could illicit a cure for sickle cell disease (SCD), but many barriers to access remain, namely cost, experts reported during a recent webinar sponsored by the National Heart, Lung, and Blood Institute.

Pogonic/Getty Images

At present, allogeneic hematopoietic stem cell transplant remains the only curative therapy available for patients with SCD. Newer transplant techniques include the use of mobilized blood stem cells, where stem cells are collected from the circulation using blood cell growth factors, explained Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

The most promising experimental gene therapies currently undergoing clinical development are gene-addition and gene-editing therapies, he said. Another technique, in vivo gene editing to correct the sickle mutation, is also being investigated, but has not yet reached clinical development.
 

Gene-addition therapy

Gene-addition therapy is a technique where a fetal hemoglobin (HbF) or anti-sickling beta-hemoglobin gene is inserted into a hematopoietic stem cell to illicit a curative effect. In this technique, the corrective gene is harvested from a patient’s own blood stem cells.

In patients with SCD, when HbF levels are elevated, the likelihood of sickling is reduced, resulting in a milder form of disease. As a result, raising HbF levels is a therapeutic target that forms the basis of several ongoing clinical studies.

The technique involves packaging an HbF rescue gene into a viral vector and coincubating the vector with a patient’s own blood stem cells. Subsequently, the corrected stem cells are injected back into the patient to produce higher levels of HbF.

The ongoing phase 1/2 HGB-206 clinical study is evaluating this technique in patients aged 12-50 years with severe SCD in multiple centers throughout Europe and the United States.

In those treated thus far, initial results appear promising, Dr. Walters reported, with one patient experiencing a rise in Hb levels from 10.7 g/dL at 3 months to 15.0 g/dL at 15 months follow-up.

Dr. Walters also reported that some of these patients no longer exhibit any signs or symptoms of SCD, such as anemia or painful adverse events. While these initial findings are compelling, whether these benefits will be maintained is still unknown.

“While it’s too early to call this a cure, if [these results] could be extended for 5, 10, or 15 years, I think everyone would agree that this would be a cure,” he said.

This technique could be universally available, he said, since a patient’s own blood stem cells are used. Other complications, such as graft-versus-host disease (GVHD) or immune-related reactions, are negated with this form of therapy, he said.

Recent evidence has demonstrated that only about 20% of donor stem cells need to be corrected to illicit a very strong effect. This principle is now being applied in gene-editing techniques, as correcting every gene in every stem cell would be very challenging, Dr. Walters explained.
 

Gene editing

Another technique being investigated in SCD is gene editing, in which the fetal hemoglobin gene is “reawakened,” or other techniques are used to correct the sickle gene directly, such as CRISPR-Cas9 technology, Dr. Walters said.

In this technique, the Cas9 protein makes a cut and repairs an individual’s genomic DNA by inserting a strand of corrected donor DNA. The novel technology would allow for targeted genome editing that is specific to the SCD patient.

Currently, this experimental therapy is being investigated in preclinical studies. Dr. Walters said that he and his colleagues hope to begin enrolling patients in clinical trials within the next 1-2 years.

But while some gene therapies have been approved in other disorders, such as spinal muscle atrophy, a limiting factor to widespread availability is cost. Despite promising initial results in SCD, the affordability of future gene therapies will be a key factor to universal access, Dr. Walters said.
 

The Cure Sickle Cell Initiative

Traci Mondoro, PhD, chief of the Translational Blood Science and Resources Branch at NHLBI, explained that the NHLBI has funded a large proportion of the research that has formed the basis of several genetically based clinical studies.

One of the primary goals of the Cure Sickle Cell Initiative is to bridge the gap between new research and the SCD community. Their aim is to improve access for patients to participate in genetically based studies to advance cures.

The comprehensive approach is intended to fill in existing gaps by funding breakthrough research in both academic and private settings.

By establishing partnerships with key stakeholders, institutions, and patient groups, Dr. Mondoro said they hope to increase patient participation in clinical trials involving curative therapies. In the future, they also intend to establish a large body of evidence to provide adequate safety data to study these therapies in pediatric populations.

Dr. Walters and Dr. Mondoro did not provide information on financial disclosures.

Early results indicate experimental gene therapies could illicit a cure for sickle cell disease (SCD), but many barriers to access remain, namely cost, experts reported during a recent webinar sponsored by the National Heart, Lung, and Blood Institute.

Pogonic/Getty Images

At present, allogeneic hematopoietic stem cell transplant remains the only curative therapy available for patients with SCD. Newer transplant techniques include the use of mobilized blood stem cells, where stem cells are collected from the circulation using blood cell growth factors, explained Mark Walters, MD, of UCSF Benioff Children’s Hospital Oakland in California.

The most promising experimental gene therapies currently undergoing clinical development are gene-addition and gene-editing therapies, he said. Another technique, in vivo gene editing to correct the sickle mutation, is also being investigated, but has not yet reached clinical development.
 

Gene-addition therapy

Gene-addition therapy is a technique where a fetal hemoglobin (HbF) or anti-sickling beta-hemoglobin gene is inserted into a hematopoietic stem cell to illicit a curative effect. In this technique, the corrective gene is harvested from a patient’s own blood stem cells.

In patients with SCD, when HbF levels are elevated, the likelihood of sickling is reduced, resulting in a milder form of disease. As a result, raising HbF levels is a therapeutic target that forms the basis of several ongoing clinical studies.

The technique involves packaging an HbF rescue gene into a viral vector and coincubating the vector with a patient’s own blood stem cells. Subsequently, the corrected stem cells are injected back into the patient to produce higher levels of HbF.

The ongoing phase 1/2 HGB-206 clinical study is evaluating this technique in patients aged 12-50 years with severe SCD in multiple centers throughout Europe and the United States.

In those treated thus far, initial results appear promising, Dr. Walters reported, with one patient experiencing a rise in Hb levels from 10.7 g/dL at 3 months to 15.0 g/dL at 15 months follow-up.

Dr. Walters also reported that some of these patients no longer exhibit any signs or symptoms of SCD, such as anemia or painful adverse events. While these initial findings are compelling, whether these benefits will be maintained is still unknown.

“While it’s too early to call this a cure, if [these results] could be extended for 5, 10, or 15 years, I think everyone would agree that this would be a cure,” he said.

This technique could be universally available, he said, since a patient’s own blood stem cells are used. Other complications, such as graft-versus-host disease (GVHD) or immune-related reactions, are negated with this form of therapy, he said.

Recent evidence has demonstrated that only about 20% of donor stem cells need to be corrected to illicit a very strong effect. This principle is now being applied in gene-editing techniques, as correcting every gene in every stem cell would be very challenging, Dr. Walters explained.
 

Gene editing

Another technique being investigated in SCD is gene editing, in which the fetal hemoglobin gene is “reawakened,” or other techniques are used to correct the sickle gene directly, such as CRISPR-Cas9 technology, Dr. Walters said.

In this technique, the Cas9 protein makes a cut and repairs an individual’s genomic DNA by inserting a strand of corrected donor DNA. The novel technology would allow for targeted genome editing that is specific to the SCD patient.

Currently, this experimental therapy is being investigated in preclinical studies. Dr. Walters said that he and his colleagues hope to begin enrolling patients in clinical trials within the next 1-2 years.

But while some gene therapies have been approved in other disorders, such as spinal muscle atrophy, a limiting factor to widespread availability is cost. Despite promising initial results in SCD, the affordability of future gene therapies will be a key factor to universal access, Dr. Walters said.
 

The Cure Sickle Cell Initiative

Traci Mondoro, PhD, chief of the Translational Blood Science and Resources Branch at NHLBI, explained that the NHLBI has funded a large proportion of the research that has formed the basis of several genetically based clinical studies.

One of the primary goals of the Cure Sickle Cell Initiative is to bridge the gap between new research and the SCD community. Their aim is to improve access for patients to participate in genetically based studies to advance cures.

The comprehensive approach is intended to fill in existing gaps by funding breakthrough research in both academic and private settings.

By establishing partnerships with key stakeholders, institutions, and patient groups, Dr. Mondoro said they hope to increase patient participation in clinical trials involving curative therapies. In the future, they also intend to establish a large body of evidence to provide adequate safety data to study these therapies in pediatric populations.

Dr. Walters and Dr. Mondoro did not provide information on financial disclosures.

The Food and Drug Administration has approved Zolgensma (onasemnogene abeparvovec-xioi), the first gene therapy for the treatment of infantile-onset spinal muscular atrophy in children aged less than 2 years.

The FDA granted the approval of Zolgensma to AveXis Inc.

Spinal muscular atrophy (SMA) is a genetic disorder caused by a mutation in the SMN1 gene, which encodes the survival motor neuron protein. This protein is necessary for motor function throughout the body; without it, motor neurons die, causing severe, often fatal muscle weakness. Infantile-onset SMA is the most severe and most common form of the disease; children will have difficulty holding their head up, swallowing, or breathing. Symptoms can be present at birth or appear by 6 months.

FDA approval of Zolgensma is based on results of a pair of clinical trials – one ongoing, one completed – comprising 36 patients with infantile-onset SMA aged between 2 weeks and 8 months at study entry. Of the 21 patients initially enrolled in the ongoing trial, 19 remain, aged between 9.4 and 18.5 months; most of these patients are at least 14 months. Compared with natural disease course, patients treated with Zolgensma are more likely to reach developmental motor milestones such as head control and the ability to sit without support.

The most common adverse events associated with Zolgensma include elevated liver enzymes and vomiting. The labeling includes a warning that acute serious liver injury can occur, and patients with preexisting liver conditions are at a higher risk for serious liver injury. Liver function should be monitored for at least 3 months following initiation of Zolgensma treatment.

“Children with SMA experience difficulty performing essential functions of life. Most children with this disease do not survive past early childhood due to respiratory failure. Patients with SMA now have another treatment option to minimize the progression of SMA and improve survival,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved Zolgensma (onasemnogene abeparvovec-xioi), the first gene therapy for the treatment of infantile-onset spinal muscular atrophy in children aged less than 2 years.

The FDA granted the approval of Zolgensma to AveXis Inc.

Spinal muscular atrophy (SMA) is a genetic disorder caused by a mutation in the SMN1 gene, which encodes the survival motor neuron protein. This protein is necessary for motor function throughout the body; without it, motor neurons die, causing severe, often fatal muscle weakness. Infantile-onset SMA is the most severe and most common form of the disease; children will have difficulty holding their head up, swallowing, or breathing. Symptoms can be present at birth or appear by 6 months.

FDA approval of Zolgensma is based on results of a pair of clinical trials – one ongoing, one completed – comprising 36 patients with infantile-onset SMA aged between 2 weeks and 8 months at study entry. Of the 21 patients initially enrolled in the ongoing trial, 19 remain, aged between 9.4 and 18.5 months; most of these patients are at least 14 months. Compared with natural disease course, patients treated with Zolgensma are more likely to reach developmental motor milestones such as head control and the ability to sit without support.

The most common adverse events associated with Zolgensma include elevated liver enzymes and vomiting. The labeling includes a warning that acute serious liver injury can occur, and patients with preexisting liver conditions are at a higher risk for serious liver injury. Liver function should be monitored for at least 3 months following initiation of Zolgensma treatment.

“Children with SMA experience difficulty performing essential functions of life. Most children with this disease do not survive past early childhood due to respiratory failure. Patients with SMA now have another treatment option to minimize the progression of SMA and improve survival,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

[email protected]

The Food and Drug Administration has approved Zolgensma (onasemnogene abeparvovec-xioi), the first gene therapy for the treatment of infantile-onset spinal muscular atrophy in children aged less than 2 years.

The FDA granted the approval of Zolgensma to AveXis Inc.

Spinal muscular atrophy (SMA) is a genetic disorder caused by a mutation in the SMN1 gene, which encodes the survival motor neuron protein. This protein is necessary for motor function throughout the body; without it, motor neurons die, causing severe, often fatal muscle weakness. Infantile-onset SMA is the most severe and most common form of the disease; children will have difficulty holding their head up, swallowing, or breathing. Symptoms can be present at birth or appear by 6 months.

FDA approval of Zolgensma is based on results of a pair of clinical trials – one ongoing, one completed – comprising 36 patients with infantile-onset SMA aged between 2 weeks and 8 months at study entry. Of the 21 patients initially enrolled in the ongoing trial, 19 remain, aged between 9.4 and 18.5 months; most of these patients are at least 14 months. Compared with natural disease course, patients treated with Zolgensma are more likely to reach developmental motor milestones such as head control and the ability to sit without support.

The most common adverse events associated with Zolgensma include elevated liver enzymes and vomiting. The labeling includes a warning that acute serious liver injury can occur, and patients with preexisting liver conditions are at a higher risk for serious liver injury. Liver function should be monitored for at least 3 months following initiation of Zolgensma treatment.

“Children with SMA experience difficulty performing essential functions of life. Most children with this disease do not survive past early childhood due to respiratory failure. Patients with SMA now have another treatment option to minimize the progression of SMA and improve survival,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in the press release.

Find the full press release on the FDA website.

[email protected]

NEW ORLEANS – The gene therapy LentiGlobin can reduce transfusion dependence in children and young adults with non-beta⁰/beta⁰ thalassemia, according to two trials.

Jennifer Smith/MDedge News

In a phase 1/2 trial, 8 of 10 of patients achieved transfusion independence at a median follow-up of 36.0 months. In a phase 3 trial, transfusion independence was achieved by 2 of 3 patients with follow-up of at least 12 months.

Timothy S. Olson, MD, PhD, of Children’s Hospital of Philadelphia, presented results from the phase 1/2 HGB-204 trial and the phase 3 HGB-207 trial at the annual meeting of the American Society of Pediatric Hematology/Oncology.
 

Treatment

In both trials, patients received granulocyte colony-stimulating factor and plerixafor for hematopoietic stem cell mobilization. Their cells were collected via apheresis and transduced with the betibeglogene darolentivec (BB305) lentiviral vector. The patients received busulfan (for an average of 4 days) as conditioning and were infused with the transduced cells.

The manufacturing process for LentiGlobin was refined in the HGB-207 trial, which translated to a product with a higher vector copy number and higher proportion of CD34+ cells transduced, Dr. Olson said.

The median vector copy number was 3.1 in the HGB-207 trial and 0.7 in the HGB-204 trial. The median proportion of CD34+ cells transfused was 81% and 29%, respectively. The median cell dose was 7.7 x 10⁶ CD34+ cells/kg and 7.1 x 10⁶ CD34+ cells/kg, respectively.

HGB-204 patients and efficacy

The HGB-204 trial included 10 patients with non-beta⁰/beta⁰ genotypes – 6 with beta^E/beta⁰, 1 with beta⁺/beta⁰, 2 with beta⁺/beta⁺, and 1 with an “other” genotype.

The patients’ median age at consent was 19.5 years (range, 16-34). The annualized median prestudy red blood cell (RBC) transfusion volume was 151 mL/kg per year.


At a median follow-up of 36 months, 8 of the 10 patients achieved transfusion independence. The median duration of transfusion independence was 38 months. The median weighted average hemoglobin during transfusion independence was 10.2 g/dL.

“Two patients did not achieve transfusion independence, and both patients were on the lower end of the spectrum both in terms of vector copy number per cell and the percentage of CD34+ cells that were successfully transduced,” Dr. Olson said. “Both patients actually experienced a reduction in the annualized transfusion volume requirements of between 43% and 77%.”

HGB-207 patients and efficacy

The HGB-207 trial included 16 patients with non-beta⁰/beta⁰ genotypes – 6 with beta^E/beta⁰, 7 with beta⁺/beta⁰, and 3 with the beta⁺/beta⁺ genotype.

The patients’ median age at consent was 19 years . The annualized median prestudy RBC transfusion volume was 192 mL/kg per year.

The median follow-up in this trial is 9.3 months. Ten of 11 patients with at least 3 months of follow-up are transfusion-free with hemoglobin levels greater than 11 g/dL.

Two patients have achieved transfusion independence according to the protocol definition, which is weighted average hemoglobin of 9 g/dL or greater without any RBC transfusions for at least 12 months.

“In the one patient in this study who did not achieve transfusion independence, the vector-derived hemoglobin was quite low, and this correlated with a very low vector copy number seen in circulating peripheral blood mononuclear cells,” Dr. Olson said.

It isn’t clear why this occurred, however, as the vector copy number wasn’t especially low in the LentiGlobin product the patient received. Therefore, the researchers are still investigating why this patient failed to achieve transfusion independence.

Safety in both trials

“Very importantly, there were no deaths, there were no engraftment failures, there was no evidence of vector-mediated replication-competent lentivirus, and integration site analysis revealed no evidence of clonal dominance,” Dr. Olson said.

He added that most of the grade 3 or greater adverse events seen in both trials were directly attributable to busulfan-based myeloablative conditioning, including four episodes of veno-occlusive disease.

Nonhematologic grade 3 or higher adverse events in HGB-204 included stomatitis (n = 8), febrile neutropenia (n = 6), irregular menstruation (n = 3), pharyngeal inflammation (n = 2), and veno-occlusive liver disease (n = 1).

Nonhematologic grade 3 or higher adverse events in HGB-207 included stomatitis (n = 9), febrile neutropenia (n = 4), pharyngeal inflammation (n = 2), epistaxis (n = 3), pyrexia (n = 3), veno-occlusive liver disease (n = 3), ALT increase (n = 2), bilirubin increase (n = 2), and hypoxia (n = 2).

One patient in HGB-207 had grade 3 thrombocytopenia considered possibly related to LentiGlobin.

Dr. Olson reported advisory board engagement with bluebird bio, which sponsored both trials.

[email protected]

SOURCE: Olson TS et al. ASPHO 2019. Abstract 2002.

NEW ORLEANS – The gene therapy LentiGlobin can reduce transfusion dependence in children and young adults with non-beta⁰/beta⁰ thalassemia, according to two trials.

Jennifer Smith/MDedge News

In a phase 1/2 trial, 8 of 10 of patients achieved transfusion independence at a median follow-up of 36.0 months. In a phase 3 trial, transfusion independence was achieved by 2 of 3 patients with follow-up of at least 12 months.

Timothy S. Olson, MD, PhD, of Children’s Hospital of Philadelphia, presented results from the phase 1/2 HGB-204 trial and the phase 3 HGB-207 trial at the annual meeting of the American Society of Pediatric Hematology/Oncology.
 

Treatment

In both trials, patients received granulocyte colony-stimulating factor and plerixafor for hematopoietic stem cell mobilization. Their cells were collected via apheresis and transduced with the betibeglogene darolentivec (BB305) lentiviral vector. The patients received busulfan (for an average of 4 days) as conditioning and were infused with the transduced cells.

The manufacturing process for LentiGlobin was refined in the HGB-207 trial, which translated to a product with a higher vector copy number and higher proportion of CD34+ cells transduced, Dr. Olson said.

The median vector copy number was 3.1 in the HGB-207 trial and 0.7 in the HGB-204 trial. The median proportion of CD34+ cells transfused was 81% and 29%, respectively. The median cell dose was 7.7 x 10⁶ CD34+ cells/kg and 7.1 x 10⁶ CD34+ cells/kg, respectively.

HGB-204 patients and efficacy

The HGB-204 trial included 10 patients with non-beta⁰/beta⁰ genotypes – 6 with beta^E/beta⁰, 1 with beta⁺/beta⁰, 2 with beta⁺/beta⁺, and 1 with an “other” genotype.

The patients’ median age at consent was 19.5 years (range, 16-34). The annualized median prestudy red blood cell (RBC) transfusion volume was 151 mL/kg per year.


At a median follow-up of 36 months, 8 of the 10 patients achieved transfusion independence. The median duration of transfusion independence was 38 months. The median weighted average hemoglobin during transfusion independence was 10.2 g/dL.

“Two patients did not achieve transfusion independence, and both patients were on the lower end of the spectrum both in terms of vector copy number per cell and the percentage of CD34+ cells that were successfully transduced,” Dr. Olson said. “Both patients actually experienced a reduction in the annualized transfusion volume requirements of between 43% and 77%.”

HGB-207 patients and efficacy

The HGB-207 trial included 16 patients with non-beta⁰/beta⁰ genotypes – 6 with beta^E/beta⁰, 7 with beta⁺/beta⁰, and 3 with the beta⁺/beta⁺ genotype.

The patients’ median age at consent was 19 years . The annualized median prestudy RBC transfusion volume was 192 mL/kg per year.

The median follow-up in this trial is 9.3 months. Ten of 11 patients with at least 3 months of follow-up are transfusion-free with hemoglobin levels greater than 11 g/dL.

Two patients have achieved transfusion independence according to the protocol definition, which is weighted average hemoglobin of 9 g/dL or greater without any RBC transfusions for at least 12 months.

“In the one patient in this study who did not achieve transfusion independence, the vector-derived hemoglobin was quite low, and this correlated with a very low vector copy number seen in circulating peripheral blood mononuclear cells,” Dr. Olson said.

It isn’t clear why this occurred, however, as the vector copy number wasn’t especially low in the LentiGlobin product the patient received. Therefore, the researchers are still investigating why this patient failed to achieve transfusion independence.

Safety in both trials

“Very importantly, there were no deaths, there were no engraftment failures, there was no evidence of vector-mediated replication-competent lentivirus, and integration site analysis revealed no evidence of clonal dominance,” Dr. Olson said.

He added that most of the grade 3 or greater adverse events seen in both trials were directly attributable to busulfan-based myeloablative conditioning, including four episodes of veno-occlusive disease.

Nonhematologic grade 3 or higher adverse events in HGB-204 included stomatitis (n = 8), febrile neutropenia (n = 6), irregular menstruation (n = 3), pharyngeal inflammation (n = 2), and veno-occlusive liver disease (n = 1).

Nonhematologic grade 3 or higher adverse events in HGB-207 included stomatitis (n = 9), febrile neutropenia (n = 4), pharyngeal inflammation (n = 2), epistaxis (n = 3), pyrexia (n = 3), veno-occlusive liver disease (n = 3), ALT increase (n = 2), bilirubin increase (n = 2), and hypoxia (n = 2).

One patient in HGB-207 had grade 3 thrombocytopenia considered possibly related to LentiGlobin.

Dr. Olson reported advisory board engagement with bluebird bio, which sponsored both trials.

[email protected]

SOURCE: Olson TS et al. ASPHO 2019. Abstract 2002.

NEW ORLEANS – The gene therapy LentiGlobin can reduce transfusion dependence in children and young adults with non-beta⁰/beta⁰ thalassemia, according to two trials.

Jennifer Smith/MDedge News

In a phase 1/2 trial, 8 of 10 of patients achieved transfusion independence at a median follow-up of 36.0 months. In a phase 3 trial, transfusion independence was achieved by 2 of 3 patients with follow-up of at least 12 months.

Timothy S. Olson, MD, PhD, of Children’s Hospital of Philadelphia, presented results from the phase 1/2 HGB-204 trial and the phase 3 HGB-207 trial at the annual meeting of the American Society of Pediatric Hematology/Oncology.
 

Treatment

In both trials, patients received granulocyte colony-stimulating factor and plerixafor for hematopoietic stem cell mobilization. Their cells were collected via apheresis and transduced with the betibeglogene darolentivec (BB305) lentiviral vector. The patients received busulfan (for an average of 4 days) as conditioning and were infused with the transduced cells.

The manufacturing process for LentiGlobin was refined in the HGB-207 trial, which translated to a product with a higher vector copy number and higher proportion of CD34+ cells transduced, Dr. Olson said.

The median vector copy number was 3.1 in the HGB-207 trial and 0.7 in the HGB-204 trial. The median proportion of CD34+ cells transfused was 81% and 29%, respectively. The median cell dose was 7.7 x 10⁶ CD34+ cells/kg and 7.1 x 10⁶ CD34+ cells/kg, respectively.

HGB-204 patients and efficacy

The HGB-204 trial included 10 patients with non-beta⁰/beta⁰ genotypes – 6 with beta^E/beta⁰, 1 with beta⁺/beta⁰, 2 with beta⁺/beta⁺, and 1 with an “other” genotype.

The patients’ median age at consent was 19.5 years (range, 16-34). The annualized median prestudy red blood cell (RBC) transfusion volume was 151 mL/kg per year.


At a median follow-up of 36 months, 8 of the 10 patients achieved transfusion independence. The median duration of transfusion independence was 38 months. The median weighted average hemoglobin during transfusion independence was 10.2 g/dL.

“Two patients did not achieve transfusion independence, and both patients were on the lower end of the spectrum both in terms of vector copy number per cell and the percentage of CD34+ cells that were successfully transduced,” Dr. Olson said. “Both patients actually experienced a reduction in the annualized transfusion volume requirements of between 43% and 77%.”

HGB-207 patients and efficacy

The HGB-207 trial included 16 patients with non-beta⁰/beta⁰ genotypes – 6 with beta^E/beta⁰, 7 with beta⁺/beta⁰, and 3 with the beta⁺/beta⁺ genotype.

The patients’ median age at consent was 19 years . The annualized median prestudy RBC transfusion volume was 192 mL/kg per year.

The median follow-up in this trial is 9.3 months. Ten of 11 patients with at least 3 months of follow-up are transfusion-free with hemoglobin levels greater than 11 g/dL.

Two patients have achieved transfusion independence according to the protocol definition, which is weighted average hemoglobin of 9 g/dL or greater without any RBC transfusions for at least 12 months.

“In the one patient in this study who did not achieve transfusion independence, the vector-derived hemoglobin was quite low, and this correlated with a very low vector copy number seen in circulating peripheral blood mononuclear cells,” Dr. Olson said.

It isn’t clear why this occurred, however, as the vector copy number wasn’t especially low in the LentiGlobin product the patient received. Therefore, the researchers are still investigating why this patient failed to achieve transfusion independence.

Safety in both trials

“Very importantly, there were no deaths, there were no engraftment failures, there was no evidence of vector-mediated replication-competent lentivirus, and integration site analysis revealed no evidence of clonal dominance,” Dr. Olson said.

He added that most of the grade 3 or greater adverse events seen in both trials were directly attributable to busulfan-based myeloablative conditioning, including four episodes of veno-occlusive disease.

Nonhematologic grade 3 or higher adverse events in HGB-204 included stomatitis (n = 8), febrile neutropenia (n = 6), irregular menstruation (n = 3), pharyngeal inflammation (n = 2), and veno-occlusive liver disease (n = 1).

Nonhematologic grade 3 or higher adverse events in HGB-207 included stomatitis (n = 9), febrile neutropenia (n = 4), pharyngeal inflammation (n = 2), epistaxis (n = 3), pyrexia (n = 3), veno-occlusive liver disease (n = 3), ALT increase (n = 2), bilirubin increase (n = 2), and hypoxia (n = 2).

One patient in HGB-207 had grade 3 thrombocytopenia considered possibly related to LentiGlobin.

Dr. Olson reported advisory board engagement with bluebird bio, which sponsored both trials.

[email protected]

SOURCE: Olson TS et al. ASPHO 2019. Abstract 2002.

The National Institutes of Health has released an amended guideline on research involving gene therapy.

As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.

We previously covered this story; find our coverage at the link below.

[email protected]

The National Institutes of Health has released an amended guideline on research involving gene therapy.

As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.

We previously covered this story; find our coverage at the link below.

[email protected]

The National Institutes of Health has released an amended guideline on research involving gene therapy.

As part of the streamlining process, the Recombinant DNA Advisory Committee has been renamed as the Novel and Exceptional Technology and Research Advisory Committee to better align with the committee’s original intention – following and providing advice on safety and ethical issues associated with emerging biotechnologies, according to a statement from Francis S. Collins, MD, PhD, director of the NIH.

We previously covered this story; find our coverage at the link below.

[email protected]

For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.

Pogonic/Getty Images

By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.

The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.

By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.

X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.

“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”

Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.

After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.

“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.

They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.

Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.

SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.

For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.

Pogonic/Getty Images

By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.

The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.

By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.

X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.

“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”

Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.

After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.

“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.

They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.

Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.

SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.

For infants with newly diagnosed X-linked severe combined immunodeficiency (SCID-X1), lentiviral gene therapy and targeted busulfan conditioning successfully induced multilineage engraftment of transduced cells, researchers reported.

Pogonic/Getty Images

By 3-4 months after infusion, seven of eight patients had normal numbers of CD3+, CD4+, and naive CD4+ T cells; normal counts of natural killer (NK) cells; and vector marking of T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors, Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital in Memphis, and her associates reported in the New England Journal of Medicine.

The eighth infant at first lacked a sufficient T-cell response but responded to a boost of gene-corrected cells without busulfan conditioning.

By 6-12 months after infusion, IgM levels also had normalized in seven of the eight infants and showed polyclonal patterns without clonal dominance, according to the investigators. Among four infants who were able to stop intravenous immunoglobulin therapy, three responded to vaccinations with tetanus, diphtheria, pertussis, polio, and pneumococcal polysaccharide. Such restoration of humoral immunity “has not been achieved in previously reported trials of gene therapy for infants with newly diagnosed SCID-X1,” wrote the investigators of this dual-center, phase 1/2 study.

X-linked severe combined immunodeficiency – “bubble boy disease” – is characterized by a lack of T cells, NK cells, and B cells, and is caused by mutations in IL2RG. Some 80% of affected infants have no matched sibling donor for hematopoietic stem cell transplantation, and transplantation from other donors can produce an inadequate response and graft-versus-host disease. Prior attempts at gene therapy with gamma-retroviral vectors had led to vector-induced leukemia or had failed to induce humoral immunity or normal NK cell production.

“Our new lentiviral vector gene therapy combined with nonmyeloablative busulfan conditioning has been successful in restoring immunity in five patients 7-23 years of age in whom a previous allogeneic hematopoietic stem cell transplantation for SCID-X1 had failed,” the investigators wrote. “We hypothesized that the combination of this lentiviral vector and low-exposure busulfan administered by means of pharmacokinetic dose targeting would be safe and effective as the primary treatment in infants with newly diagnosed SCID-X1.”

Their protocol included one to two daily intravenous doses of busulfan, targeting a cumulative area under the curve of 22 mg per hr/L. They calculated the first dose by weight and age using a population-based pharmacokinetic model and adjusted the second dose based on first-dose pharmacokinetics.

After a median of 16.4 months, all infants continued to grow normally and cleared previous infections, and there were no unanticipated side effects from bone marrow harvest, busulfan conditioning, or cell infusion.

“It is hoped that durable, complete adaptive immunity will be achieved in the majority of the patients over time,” the researchers wrote.

They continue to follow the patients to assess therapeutic safety, immune durability, and persistence of the transferred gene in hematopoietic and immune cells.

Study funders included the American Lebanese Syrian Associated Charities, the National Institutes of Health, the California Institute of Regenerative Medicine, and the Assisi Foundation of Memphis. St. Jude Children’s Research Hospital has licensed the gene therapy and partnered with Mustang Bio to develop and commercialize it. Dr. Mamcarz reported receiving grant support from the study funders.

SOURCE: Mamcarz E et al. N Engl J Med. 2019; 380:1525-34.

Several hematology and oncology researchers will receive awards at the 2019 conference of the American Society of Pediatric Hematology/Oncology (ASPHO), which takes place May 1-4.

Loretta Li, MD, of Boston Children’s Hospital/Dana-Farber Cancer Institute, and Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, will receive Young Investigator awards at the conference.

Dr. Sharma is conducting research investigating the genetic regulation of fetal hemoglobin and developing transplant and gene therapy trials for patients with sickle cell disease. Dr. Li is studying the activity of JAK2 inhibitors, as well as mechanisms of response and resistance to these drugs, in leukemias.

Elliott Vichinsky, MD, of UCSF Benioff Children’s Hospital Oakland in California, will receive ASPHO’s Distinguished Career Award. Dr. Vichinsky has helped implement newborn screening programs for blood diseases, developed techniques to make blood safer for chronically transfused patients, and conducted research that furthered the development of drugs used to treat iron overload.

Wilbur Lam, MD, PhD, of Aflac Cancer & Blood Disorders Center/Emory University in Atlanta, has won the Frank A. Oski Memorial Lectureship. He will present “Development and Clinical Translation of Engineered Microsystems for Hematologic Applications” on May 2.

Dr. Lam’s research has focused on using nanomechanical and microfluidic engineering approaches to study blood cells, endothelial cells, and thrombosis. Dr. Lam and his lab have created “microvasculature-on-a-chip” models of blood diseases and a smartphone app that can detect and monitor anemia.

Kenneth McClain, MD, PhD, of Texas Children’s Hospital/Baylor University in Houston, has won the 2019 George R. Buchanan Lectureship. Dr. McClain will present “An Oncogene-Driven Orphan Disease: A Short History of Langerhans Cell Histiocytosis” on May 2.

Dr. McClain’s research has focused on Langerhans cell histiocytosis and related disorders. He has served as a founding member and president of the Histiocyte Society, and he organizes yearly events to provide information on Langerhans cell histiocytosis to patients and their families.

Smita Bhatia, MD, of University of Alabama, Birmingham, has won the Childhood Cancer Survivorship Award for Excellence. Her research has focused on health‐related outcomes in cancer survivors and the pathogenesis of these outcomes. Dr. Bhatia has developed models that can identify high-risk cancer survivors and interventions that can reduce complications among cancer survivors.
 

Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Several hematology and oncology researchers will receive awards at the 2019 conference of the American Society of Pediatric Hematology/Oncology (ASPHO), which takes place May 1-4.

Loretta Li, MD, of Boston Children’s Hospital/Dana-Farber Cancer Institute, and Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, will receive Young Investigator awards at the conference.

Dr. Sharma is conducting research investigating the genetic regulation of fetal hemoglobin and developing transplant and gene therapy trials for patients with sickle cell disease. Dr. Li is studying the activity of JAK2 inhibitors, as well as mechanisms of response and resistance to these drugs, in leukemias.

Elliott Vichinsky, MD, of UCSF Benioff Children’s Hospital Oakland in California, will receive ASPHO’s Distinguished Career Award. Dr. Vichinsky has helped implement newborn screening programs for blood diseases, developed techniques to make blood safer for chronically transfused patients, and conducted research that furthered the development of drugs used to treat iron overload.

Wilbur Lam, MD, PhD, of Aflac Cancer & Blood Disorders Center/Emory University in Atlanta, has won the Frank A. Oski Memorial Lectureship. He will present “Development and Clinical Translation of Engineered Microsystems for Hematologic Applications” on May 2.

Dr. Lam’s research has focused on using nanomechanical and microfluidic engineering approaches to study blood cells, endothelial cells, and thrombosis. Dr. Lam and his lab have created “microvasculature-on-a-chip” models of blood diseases and a smartphone app that can detect and monitor anemia.

Kenneth McClain, MD, PhD, of Texas Children’s Hospital/Baylor University in Houston, has won the 2019 George R. Buchanan Lectureship. Dr. McClain will present “An Oncogene-Driven Orphan Disease: A Short History of Langerhans Cell Histiocytosis” on May 2.

Dr. McClain’s research has focused on Langerhans cell histiocytosis and related disorders. He has served as a founding member and president of the Histiocyte Society, and he organizes yearly events to provide information on Langerhans cell histiocytosis to patients and their families.

Smita Bhatia, MD, of University of Alabama, Birmingham, has won the Childhood Cancer Survivorship Award for Excellence. Her research has focused on health‐related outcomes in cancer survivors and the pathogenesis of these outcomes. Dr. Bhatia has developed models that can identify high-risk cancer survivors and interventions that can reduce complications among cancer survivors.
 

Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Several hematology and oncology researchers will receive awards at the 2019 conference of the American Society of Pediatric Hematology/Oncology (ASPHO), which takes place May 1-4.

Loretta Li, MD, of Boston Children’s Hospital/Dana-Farber Cancer Institute, and Akshay Sharma, MBBS, of St. Jude Children’s Research Hospital in Memphis, will receive Young Investigator awards at the conference.

Dr. Sharma is conducting research investigating the genetic regulation of fetal hemoglobin and developing transplant and gene therapy trials for patients with sickle cell disease. Dr. Li is studying the activity of JAK2 inhibitors, as well as mechanisms of response and resistance to these drugs, in leukemias.

Elliott Vichinsky, MD, of UCSF Benioff Children’s Hospital Oakland in California, will receive ASPHO’s Distinguished Career Award. Dr. Vichinsky has helped implement newborn screening programs for blood diseases, developed techniques to make blood safer for chronically transfused patients, and conducted research that furthered the development of drugs used to treat iron overload.

Wilbur Lam, MD, PhD, of Aflac Cancer & Blood Disorders Center/Emory University in Atlanta, has won the Frank A. Oski Memorial Lectureship. He will present “Development and Clinical Translation of Engineered Microsystems for Hematologic Applications” on May 2.

Dr. Lam’s research has focused on using nanomechanical and microfluidic engineering approaches to study blood cells, endothelial cells, and thrombosis. Dr. Lam and his lab have created “microvasculature-on-a-chip” models of blood diseases and a smartphone app that can detect and monitor anemia.

Kenneth McClain, MD, PhD, of Texas Children’s Hospital/Baylor University in Houston, has won the 2019 George R. Buchanan Lectureship. Dr. McClain will present “An Oncogene-Driven Orphan Disease: A Short History of Langerhans Cell Histiocytosis” on May 2.

Dr. McClain’s research has focused on Langerhans cell histiocytosis and related disorders. He has served as a founding member and president of the Histiocyte Society, and he organizes yearly events to provide information on Langerhans cell histiocytosis to patients and their families.

Smita Bhatia, MD, of University of Alabama, Birmingham, has won the Childhood Cancer Survivorship Award for Excellence. Her research has focused on health‐related outcomes in cancer survivors and the pathogenesis of these outcomes. Dr. Bhatia has developed models that can identify high-risk cancer survivors and interventions that can reduce complications among cancer survivors.
 

Movers in Medicine highlights career moves and personal achievements by hematologists and oncologists. Did you switch jobs, take on a new role, climb a mountain? Tell us all about it at [email protected], and you could be featured in Movers in Medicine.

[email protected]

Interim data suggest SB-525, an investigational gene therapy, may be safe and effective for patients with severe hemophilia A.

In the phase 1/2 Alta trial, SB-525 produced dose-dependent increases in factor VIII activity, with two of eight patients achieving normal factor VIII levels.

In addition, SB-525 was considered well tolerated. One patient did experience treatment-related serious adverse events – hypotension and fever – but these resolved within 24 hours.

Sangamo Therapeutics and Pfizer recently released these data in a press release and conference call.

The data include eight patients with severe hemophilia A who received SB-525 at 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg.

Patient 1 (9e11 vg/kg), Patient 2 (9e11 vg/kg), and Patient 3 (2e12 vg/kg) did not experience clinically relevant increases in factor VIII levels and still require prophylactic recombinant factor VIII therapy.

Patient 4 (2e12 vg/kg) and Patient 5 (1e13 vg/kg) discontinued factor VIII therapy but have experienced spontaneous bleeds. Patient 4 had three bleeds in 48 weeks of follow-up, and Patient 5 had two bleeds in 40 weeks of follow-up.

Patient 6 (1e13 vg/kg), Patient 7 (3e13 vg/kg), and Patient 8 (3e13 vg/kg) have stopped factor VIII therapy and remain free of spontaneous bleeds at 28 weeks, 12 weeks, and 6 weeks of follow-up, respectively.

Patients 7 and 8 have achieved normal factor VIII levels. At 6 weeks, their factor VIII levels reached 140% and 94% of normal, respectively, according to a one-stage clotting assay, and 93% and 65%, respectively, according to a chromogenic assay.

“It appears the patients achieve their peak factor level at week 5 to 7 and maintain that level,” Edward Conner, MD, chief medical officer of Sangamo, said during the conference call.

The adverse events observed in this trial include grade 1 tachycardia (n = 1), grade 1 fatigue (n = 1), grade 1 alanine aminotransferase increase (n = 3), grade 1 myalgia (n = 1), grade 2 pyrexia (n = 2), and grade 3 hypotension (n = 1).

“These interim results indicate that SB-525 has the potential to comprise a well-tolerated, reliable, and predictable treatment, features that we believe will be a hallmark of the future gene therapy treatment of hemophilia A,” Dr. Conner said during the call.

Sangamo and Pfizer are enrolling additional patients in this trial, with the goal of expanding the 3e13 vg/kg cohort by up to five patients. The companies plan to present longer-term follow-up data at an upcoming scientific meeting.

The Alta trial is sponsored by Sangamo Therapeutics in collaboration with Pfizer.

[email protected]

Interim data suggest SB-525, an investigational gene therapy, may be safe and effective for patients with severe hemophilia A.

In the phase 1/2 Alta trial, SB-525 produced dose-dependent increases in factor VIII activity, with two of eight patients achieving normal factor VIII levels.

In addition, SB-525 was considered well tolerated. One patient did experience treatment-related serious adverse events – hypotension and fever – but these resolved within 24 hours.

Sangamo Therapeutics and Pfizer recently released these data in a press release and conference call.

The data include eight patients with severe hemophilia A who received SB-525 at 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg.

Patient 1 (9e11 vg/kg), Patient 2 (9e11 vg/kg), and Patient 3 (2e12 vg/kg) did not experience clinically relevant increases in factor VIII levels and still require prophylactic recombinant factor VIII therapy.

Patient 4 (2e12 vg/kg) and Patient 5 (1e13 vg/kg) discontinued factor VIII therapy but have experienced spontaneous bleeds. Patient 4 had three bleeds in 48 weeks of follow-up, and Patient 5 had two bleeds in 40 weeks of follow-up.

Patient 6 (1e13 vg/kg), Patient 7 (3e13 vg/kg), and Patient 8 (3e13 vg/kg) have stopped factor VIII therapy and remain free of spontaneous bleeds at 28 weeks, 12 weeks, and 6 weeks of follow-up, respectively.

Patients 7 and 8 have achieved normal factor VIII levels. At 6 weeks, their factor VIII levels reached 140% and 94% of normal, respectively, according to a one-stage clotting assay, and 93% and 65%, respectively, according to a chromogenic assay.

“It appears the patients achieve their peak factor level at week 5 to 7 and maintain that level,” Edward Conner, MD, chief medical officer of Sangamo, said during the conference call.

The adverse events observed in this trial include grade 1 tachycardia (n = 1), grade 1 fatigue (n = 1), grade 1 alanine aminotransferase increase (n = 3), grade 1 myalgia (n = 1), grade 2 pyrexia (n = 2), and grade 3 hypotension (n = 1).

“These interim results indicate that SB-525 has the potential to comprise a well-tolerated, reliable, and predictable treatment, features that we believe will be a hallmark of the future gene therapy treatment of hemophilia A,” Dr. Conner said during the call.

Sangamo and Pfizer are enrolling additional patients in this trial, with the goal of expanding the 3e13 vg/kg cohort by up to five patients. The companies plan to present longer-term follow-up data at an upcoming scientific meeting.

The Alta trial is sponsored by Sangamo Therapeutics in collaboration with Pfizer.

[email protected]

Interim data suggest SB-525, an investigational gene therapy, may be safe and effective for patients with severe hemophilia A.

In the phase 1/2 Alta trial, SB-525 produced dose-dependent increases in factor VIII activity, with two of eight patients achieving normal factor VIII levels.

In addition, SB-525 was considered well tolerated. One patient did experience treatment-related serious adverse events – hypotension and fever – but these resolved within 24 hours.

Sangamo Therapeutics and Pfizer recently released these data in a press release and conference call.

The data include eight patients with severe hemophilia A who received SB-525 at 9e11 vg/kg, 2e12 vg/kg, 1e13 vg/kg, and 3e13 vg/kg.

Patient 1 (9e11 vg/kg), Patient 2 (9e11 vg/kg), and Patient 3 (2e12 vg/kg) did not experience clinically relevant increases in factor VIII levels and still require prophylactic recombinant factor VIII therapy.

Patient 4 (2e12 vg/kg) and Patient 5 (1e13 vg/kg) discontinued factor VIII therapy but have experienced spontaneous bleeds. Patient 4 had three bleeds in 48 weeks of follow-up, and Patient 5 had two bleeds in 40 weeks of follow-up.

Patient 6 (1e13 vg/kg), Patient 7 (3e13 vg/kg), and Patient 8 (3e13 vg/kg) have stopped factor VIII therapy and remain free of spontaneous bleeds at 28 weeks, 12 weeks, and 6 weeks of follow-up, respectively.

Patients 7 and 8 have achieved normal factor VIII levels. At 6 weeks, their factor VIII levels reached 140% and 94% of normal, respectively, according to a one-stage clotting assay, and 93% and 65%, respectively, according to a chromogenic assay.

“It appears the patients achieve their peak factor level at week 5 to 7 and maintain that level,” Edward Conner, MD, chief medical officer of Sangamo, said during the conference call.

The adverse events observed in this trial include grade 1 tachycardia (n = 1), grade 1 fatigue (n = 1), grade 1 alanine aminotransferase increase (n = 3), grade 1 myalgia (n = 1), grade 2 pyrexia (n = 2), and grade 3 hypotension (n = 1).

“These interim results indicate that SB-525 has the potential to comprise a well-tolerated, reliable, and predictable treatment, features that we believe will be a hallmark of the future gene therapy treatment of hemophilia A,” Dr. Conner said during the call.

Sangamo and Pfizer are enrolling additional patients in this trial, with the goal of expanding the 3e13 vg/kg cohort by up to five patients. The companies plan to present longer-term follow-up data at an upcoming scientific meeting.

The Alta trial is sponsored by Sangamo Therapeutics in collaboration with Pfizer.

[email protected]

Click here to read supplement.

Gene therapy is a contemporary therapeutic intervention with recent positive results and regulatory approvals either completed or expected in the next several years for various con­ditions. In this supplement, learn more about:

• Basic principles of gene therapy
• In vivo vs ex vivo methods of gene transfer
• Vector types
• Clinical Considerations

About the Author

Click here to read supplement.

Click here to read supplement.

Gene therapy is a contemporary therapeutic intervention with recent positive results and regulatory approvals either completed or expected in the next several years for various con­ditions. In this supplement, learn more about:

• Basic principles of gene therapy
• In vivo vs ex vivo methods of gene transfer
• Vector types
• Clinical Considerations

About the Author

Click here to read supplement.

Click here to read supplement.

Gene therapy is a contemporary therapeutic intervention with recent positive results and regulatory approvals either completed or expected in the next several years for various con­ditions. In this supplement, learn more about:

• Basic principles of gene therapy
• In vivo vs ex vivo methods of gene transfer
• Vector types
• Clinical Considerations

About the Author

Click here to read supplement.