case study of gene therapy

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• INNOVATIONS IN
• 26 October 2021

Four Success Stories in Gene Therapy

• Jim Daley 0

Jim Daley is a freelance journalist from Chicago. He writes about science and health.

You can also search for this author in PubMed   Google Scholar

Credit: Design Cells/Getty images

After numerous setbacks at the turn of the century, gene therapy is treating diseases ranging from neuromuscular disorders to cancer to blindness. The success is often qualified, however. Some of these therapies have proved effective at alleviating disease but come with a high price tag and other accessibility issues: Even when people know that a protocol exists for their disease and even if they can afford it or have an insurance company that will cover the cost—which can range from $400,000 to $2 million—they may not be able to travel to the few academic centers that offer it. Other therapies alleviate symptoms but don’t eliminate the underlying cause.

“Completely curing patients is obviously going to be a huge success, but it’s not [yet] an achievable aim in a lot of situations,” says Julie Crudele, a neurologist and gene therapy researcher at the University of Washington. Still, even limited advances pave the way for ongoing progress, she adds, pointing to research in her patients who have Duchenne muscular dystrophy: “In most of these clinical trials, we learn important things.”

Thanks to that new knowledge and steadfast investigations, gene therapy researchers can now point to a growing list of successful gene therapies. Here are four of the most promising.

Gene Swaps to Prevent Vision Loss

Some babies are born with severe vision loss caused by retinal diseases that once led inevitably to total blindness. Today some of them can benefit from a gene therapy created by wife-and-husband team Jean Bennett and Albert Maguire, who are now ophthalmologists at the University of Pennsylvania.

When the pair first began researching retinal disease in 1991, none of the genes now known to cause vision loss and blindness had been identified. In 1993 researchers identified one potential target gene, RPE65 . Seven years later Bennett and Maguire tested a therapy targeting that gene in three dogs with severe vision loss—it restored vision for all three.

Part of Innovations In Gene Therapy

In humans, the inherited condition that best corresponds with the dogs’ vision loss is Leber congenital amaurosis (LCA). LCA prevents the retina, a layer of light-sensitive cells at the back of the eye, from properly reacting or sending signals to the brain when a photon strikes it. The condition can cause uncontrolled shaking of the eye (nystagmus), prevents pupils from responding to light and typically results in total blindness by age 40. Researchers have linked the disease to mutations or deletions in any one of 27 genes associated with retinal development and function. Until gene therapy, there was no cure.

Mutations in RPE65 are just one cause of inherited retinal dystrophy, but it was a cause that Bennett and Maguire could act on. The researchers used a harmless adeno-associated virus (AAV), which they programmed to find retinal cells and insert a healthy version of the gene, and injected it into a patient’s eye directly underneath the retina. In 2017, after a series of clinical trials, the Food and Drug Administration approved voretigene neparvovec-rzyl (marketed as Luxturna) for the treatment of any heritable retinal dystrophy caused by the mutated RPE65 gene, including LCA type 2 and retinitis pigmentosa, another congenital eye disease that affects photoreceptors in the retina. Luxturna was the first FDA-approved in vivo gene therapy, which is delivered to target cells inside the body (previously approved ex vivo therapies deliver the genetic material to target cells in samples collected from the body, which are then reinjected).

Spark Therapeutics, the company that makes Luxturna, estimates that about 6,000 people worldwide and between 1,000 and 2,000 in the U.S. may be eligible for its treatment—few enough that Luxturna was granted “orphan drug” status, a designation that the FDA uses to incentivize development of treatments for rare diseases. That wasn’t enough to bring the cost down. The therapy is priced at about $425,000 per injection, or nearly $1 million for both eyes. Despite the cost, Maguire says, “I have not yet seen anybody in the U.S. who hasn’t gotten access based on inability to pay.”

Those treated show significant improvement: Patients who were once unable to see clearly had their vision restored, often very quickly. Some reported that, after the injections, they could see stars for the first time.

While it is unclear how long the effects will last, follow-up data published in 2017 showed that all 20 patients treated with Luxturna in a phase 3 trial had retained their improved vision three years later. Bennett says five-year follow-up with 29 patients, which is currently undergoing peer review, showed similarly successful results. “These people can now do things they never could have dreamed of doing, and they’re more independent and enjoying life.”

Training the Immune System to Fight Cancer

Gene therapy has made inroads against cancer, too. An approach known as chimeric antigen receptor (CAR) T cell therapy works by programming a patient’s immune cells to recognize and target cells with cancerous mutations. Steven Rosenberg, chief of surgery at the National Cancer Institute, helped to develop the therapy and published the first successful results in a 2010 study for the treatment of lymphoma.

“That patient had massive amounts of disease in his chest and his belly, and he underwent a complete regression,” Rosenberg says—a regression that has now lasted 11 years and counting.

CAR T cell therapy takes advantage of white blood cells, called T cells, that serve as the first line of defense against pathogens. The approach uses a patient’s own T cells, which are removed and genetically altered so they can build receptors specific to cancer cells. Once infused back into the patient, the modified T cells, which now have the ability to recognize and attack cancerous cells, reproduce and remain on alert for future encounters.

In 2016 researchers at the University of Pennsylvania reported results from a CAR T cell treatment, called tisagenlecleucel, for acute lymphoblastic leukemia (ALL), one of the most common childhood cancers. In patients with ALL, mutations in the DNA of bone marrow cells cause them to produce massive quantities of lymphoblasts, or undeveloped white blood cells, which accumulate in the bloodstream. The disease progresses rapidly: adults face a low likelihood of cure, and fewer than half survive more than five years after diagnosis.

When directed against ALL, CAR T cells are ruthlessly efficient—a single modified T cell can kill as many as 100,000 lymphoblasts. In the University of Pennsylvania study, 29 out of 52 ALL patients treated with tisagenlecleucel went into sustained remission. Based on that study’s results, the FDA approved the therapy (produced by Novartis as Kymriah) for treating ALL, and the following year the agency approved it for use against diffuse large B cell lymphoma. The one-time procedure costs upward of $475,000.

CAR T cell therapy is not without risk. It can cause severe side effects, including cytokine release syndrome (CRS), a dangerous inflammatory response that ranges from mild flulike symptoms in less severe cases to multiorgan failure and even death. CRS isn’t specific to CAR T therapy: Researchers first observed it in the 1990s as a side effect of antibody therapies used in organ transplants. Today, with a combination of newer drugs and vigilance, doctors better understand how far they can push treatment without triggering CRS. Rosenberg says that “we know how to deal with side effects as soon as they occur, and serious illness and death from cytokine release syndrome have dropped drastically from the earliest days.”

Through 2020, the remission rate among ALL patients treated with Kymriah was about 85 percent. More than half had no relapses after a year. Novartis plans to track outcomes of all patients who received the therapy for 15 years to better understand how long it remains effective.

Precision Editing for Blood Disorders

One new arrival to the gene therapy scene is being watched particularly closely: in vivo gene editing using a system called CRISPR, which has become one of the most promising gene therapies since Jennifer Doudna and Emmanuelle Charpentier discovered it in 2012—a feat for which they shared the 2020 Nobel Prize in Chemistry. The first results from a small clinical trial aimed at treating sickle cell disease and a closely related disorder, called beta thalassemia, were published this past June.

Sickle cell disease affects millions of people worldwide and causes the production of crescent-shaped red blood cells that are stickier and more rigid than healthy cells, which can lead to anemia and life-threatening health crises. Beta thalassemia, which affects millions more, occurs when a different mutation causes someone’s body to produce less hemoglobin, the iron-rich protein that allows red blood cells to carry oxygen. Bone marrow transplants may offer a cure for those who can find matching donors, but otherwise treatments for both consist primarily of blood transfusions and medications to treat associated complications.

Both sickle cell disease and beta thalassemia are caused by heritable, single-gene mutations, making them good candidates for gene-editing therapy. The method, CRISPR-Cas9, uses DNA sequences from bacteria (clustered regularly interspaced short palindromic repeats, or CRISPR) and a CRISPR-associated enzyme (Cas for short) to edit the patient’s genome. The CRISPR sequences are transcribed onto RNA that locates and identifies DNA sequences to blame for a particular condition. When packaged together with Cas9, transcribed RNA locates the target sequence, and Cas9 snips it out of the DNA, thereby repairing or deactivating the problematic gene.

At a conference this past June, Vertex Pharmaceuticals and CRISPR Therapeutics announced unpublished results from a clinical trial of beta thalassemia and sickle cell patients treated with CTX001, a CRISPR-Cas9-based therapy. In both cases, the therapy does not shut off a target gene but instead delivers a gene that boosts production of healthy fetal hemoglobin—a gene normally turned off shortly after birth. Fifteen people with beta thalassemia were treated with CTX001; after three months or more, all 15 showed rapidly improved hemoglobin levels and no longer required blood transfusions. Seven people with severe sickle cell disease received the same treatment, all of whom showed increased levels of hemoglobin and reported at least three months without severe pain. More than a year later those improvements persisted in five subjects with beta thalassemia and two with sickle cell. The trial is ongoing, and patients are still being enrolled. A Vertex spokesperson says it hopes to enroll 45 patients in all and file for U.S. approval as early as 2022.

Derailing a Potentially Lethal Illness

Spinal muscular atrophy (SMA) is a neurodegenerative disease in which motor neurons—the nerves that control muscle movement and that connect the spinal cord to muscles and organs—degrade, malfunction and die. It is typically diagnosed in infants and toddlers. The underlying cause is a genetic mutation that inhibits production of a protein involved in building and maintaining those motor neurons.

The four types of SMA are ranked by severity and related to how much motor neuron protein a person’s cells can still produce. In the most severe or type I cases, even the most basic functions, such as breathing, sitting and swallowing, prove extremely challenging. Infants diagnosed with type I SMA have historically had a 90 percent mortality rate by one year.

Adrian Krainer, a biochemist at Cold Spring Harbor Laboratory, first grew interested in SMA when he attended a National Institutes of Health workshop in 1999. At the time, Krainer was investigating how RNA mutations cause cancer and genetic diseases when they disrupt a process called splicing, and researchers suspected that a defect in the process might be at the root of SMA. When RNA is transcribed from the DNA template, it needs to be edited or “spliced” into messenger RNA (mRNA) before it can guide protein production. During that editing process, some sequences are cut out (introns), and those that remain (exons) are strung together.

Krainer realized that there were similarities between the defects associated with SMA and one of the mechanisms he had been studying—namely, a mistake that occurs when an important exon is inadvertently lost during RNA splicing. People with SMA were missing one of these crucial gene sequences, called SMN1 .

“If we could figure out why this exon was being skipped and if we could find a solution for that, then presumably this could help all the [SMA] patients,” Krainer says. The solution he and his colleagues hit on, antisense therapy, employs single strands of synthetic nucleotides to deliver genetic instructions directly to cells in the body . In SMA’s case, the instructions induce a different motor neuron gene, SMN2 , which normally produces small amounts of the missing motor neuron protein, to produce much more of it and effectively fill in for SMN1 . The first clinical trial to test the approach began in 2010, and by 2016 the FDA approved nusinersen (marketed as Spinraza). Because the therapy does not incorporate itself into the genome, it must be administered every four months to maintain protein production. And it is staggeringly expensive: a single Spinraza treatment costs as much as $750,000 in the first year and $375,000 annually thereafter.

Since 2016, more than 10,000 people have been treated with it worldwide. Although Spinraza can’t restore completely normal motor function (a single motor neuron gene just can’t produce enough protein for that), it can help children with any of the four types of SMA live longer and more active lives. In many cases, Spinraza has improved patients’ motor function, allowing even those with more severe cases to breathe, swallow and sit upright on their own. “The most striking results are in patients who are being treated very shortly after birth, when they have a genetic diagnosis through newborn screening,” Krainer says. “Then, you can actually prevent the onset of the disease—for several years and hopefully forever.”

doi: https://doi.org/10.1038/d41586-021-02737-7

This article is part of Innovations In Gene Therapy , an editorially independent supplement produced with the financial support of third parties. About this content .

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November 1, 2021

Four Success Stories in Gene Therapy

The field is beginning to fulfill its potential. These therapies offer a glimpse of what’s to come

By Jim Daley

Design Cells Getty Images

After numerous setbacks at the turn of the century, gene therapy is treating diseases ranging from neuromuscular disorders to cancer to blindness. The success is often qualified, however. Some of these therapies have proved effective at alleviating disease but come with a high price tag and other accessibility issues: Even when people know that a protocol exists for their disease and even if they can afford it or have an insurance company that will cover the cost—which can range from $400,000 to $2 million—they may not be able to travel to the few academic centers that offer it. Other therapies alleviate symptoms but don’t eliminate the underlying cause.

“Completely curing patients is obviously going to be a huge success, but it’s not [yet] an achievable aim in a lot of situations,” says Julie Crudele, a neurologist and gene therapy researcher at the University of Washington. Still, even limited advances pave the way for ongoing progress, she adds, pointing to research in her patients who have Duchenne muscular dystrophy: “In most of these clinical trials, we learn important things.”

Thanks to that new knowledge and steadfast investigations, gene therapy researchers can now point to a growing list of successful gene therapies. Here are four of the most promising.

Gene Swaps to Prevent Vision Loss

Some babies are born with severe vision loss caused by retinal diseases that once led inevitably to total blindness. Today some of them can benefit from a gene therapy created by wife-and-husband team Jean Bennett and Albert Maguire, who are now ophthalmologists at the University of Pennsylvania.

When the pair first began researching retinal disease in 1991, none of the genes now known to cause vision loss and blindness had been identified. In 1993 researchers identified one potential target gene, RPE65 . Seven years later Bennett and Maguire tested a therapy targeting that gene in three dogs with severe vision loss—it restored vision for all three.

In humans, the inherited condition that best corresponds with the dogs’ vision loss is Leber congenital amaurosis (LCA). LCA prevents the retina, a layer of light-sensitive cells at the back of the eye, from properly reacting or sending signals to the brain when a photon strikes it. The condition can cause uncontrolled shaking of the eye (nystagmus), prevents pupils from responding to light and typically results in total blindness by age 40. Researchers have linked the disease to mutations or deletions in any one of 27 genes associated with retinal development and function. Until gene therapy, there was no cure.

Mutations in RPE65 are just one cause of inherited retinal dystrophy, but it was a cause that Bennett and Maguire could act on. The researchers used a harmless adeno-associated virus (AAV), which they programmed to find retinal cells and insert a healthy version of the gene, and injected it into a patient’s eye directly underneath the retina. In 2017, after a series of clinical trials, the Food and Drug Administration approved voretigene neparvovecrzyl (marketed as Luxturna) for the treatment of any heritable retinal dystrophy caused by the mutated RPE65 gene, including LCA type 2 and retinitis pigmentosa, another congenital eye disease that affects photoreceptors in the retina. Luxturna was the first FDA-approved in vivo gene therapy, which is delivered to target cells inside the body (previously approved ex vivo therapies deliver the genetic material to target cells in samples collected from the body, which are then reinjected).

Spark Therapeutics, the company that makes Luxturna, estimates that about 6,000 people worldwide and between 1,000 and 2,000 in the U.S. may be eligible for its treatment—few enough that Luxturna was granted “orphan drug” status, a designation that the FDA uses to incentivize development of treatments for rare diseases. That wasn’t enough to bring the cost down. The therapy is priced at about $425,000 per injection, or nearly $1 million for both eyes. Despite the cost, Maguire says, “I have not yet seen anybody in the U.S. who hasn’t gotten access based on inability to pay.”

Those treated show significant improvement: Patients who were once unable to see clearly had their vision restored, often very quickly. Some reported that, after the injections, they could see stars for the first time.

While it is unclear how long the effects will last, follow-up data published in 2017 showed that all 20 patients treated with Luxturna in a phase 3 trial had retained their improved vision three years later. Bennett says five-year follow-up with 29 patients, which is currently undergoing peer review, showed similarly successful results. “These people can now do things they never could have dreamed of doing, and they’re more independent and enjoying life.”

Training the Immune System to Fight Cancer

Gene therapy has made inroads against cancer, too. An approach known as chimeric antigen receptor (CAR) T cell therapy works by programming a patient’s immune cells to recognize and target cells with cancerous mutations. Steven Rosenberg, chief of surgery at the National Cancer Institute, helped to develop the therapy and published the first successful results in a 2010 study for the treatment of lymphoma.

“That patient had massive amounts of disease in his chest and his belly, and he underwent a complete regression,” Rosenberg says—a regression that has now lasted 11 years and counting.

CAR T cell therapy takes advantage of white blood cells, called T cells, that serve as the first line of defense against pathogens. The approach uses a patient’s own T cells, which are removed and genetically altered so they can build receptors specific to cancer cells. Once infused back into the patient, the modified T cells, which now have the ability to recognize and attack cancerous cells, reproduce and remain on alert for future encounters.

In 2016 researchers at the University of Pennsylvania reported results from a CAR T cell treatment, called tisagenlecleucel, for acute lymphoblastic leukemia (ALL), one of the most common childhood cancers. In patients with ALL, mutations in the DNA of bone marrow cells cause them to produce massive quantities of lymphoblasts, or undeveloped white blood cells, which accumulate in the bloodstream. The disease progresses rapidly: adults face a low likelihood of cure, and fewer than half survive more than five years after diagnosis.

When directed against ALL, CAR T cells are ruthlessly efficient—a single modified T cell can kill as many as 100,000 lymphoblasts. In the University of Pennsylvania study, 29 out of 52 ALL patients treated with tisagenlecleucel went into sustained remission. Based on that study’s results, the FDA approved the therapy (produced by Novartis as Kymriah) for treating ALL, and the following year the agency approved it for use against diffuse large B cell lymphoma. The one-time procedure costs upward of $475,000.

CAR T cell therapy is not without risk. It can cause severe side effects, including cytokine release syndrome (CRS), a dangerous inflammatory response that ranges from mild flulike symptoms in less severe cases to multiorgan failure and even death. CRS isn’t specific to CAR T therapy: Researchers first observed it in the 1990s as a side effect of antibody therapies used in organ transplants. Today, with a combination of newer drugs and vigilance, doctors better understand how far they can push treatment without triggering CRS. Rosenberg says that “we know how to deal with side effects as soon as they occur, and serious illness and death from cytokine release syndrome have dropped drastically from the earliest days.”

Through 2020, the remission rate among ALL patients treated with Kymriah was about 85 percent. More than half had no relapses after a year. Novartis plans to track outcomes of all patients who received the therapy for 15 years to better understand how long it remains effective.

Precision Editing for Blood Disorders

One new arrival to the gene therapy scene is being watched particularly closely: in vivo gene editing using a system called CRISPR, which has become one of the most promising gene therapies since Jennifer Doudna and Emmanuelle Charpentier discovered it in 2012—a feat for which they shared the 2020 Nobel Prize in Chemistry. The first results from a small clinical trial aimed at treating sickle cell disease and a closely related disorder, called beta thalassemia, were published this past June.

Sickle cell disease affects millions of people worldwide and causes the production of crescent-shaped red blood cells that are stickier and more rigid than healthy cells, which can lead to anemia and life-threatening health crises. Beta thalassemia, which affects millions more, occurs when a different mutation causes someone’s body to produce less hemoglobin, the iron-rich protein that allows red blood cells to carry oxygen. Bone marrow transplants may offer a cure for those who can find matching donors, but otherwise treatments for both consist primarily of blood transfusions and medications to treat associated complications.

Both sickle cell disease and beta thalassemia are caused by heritable, single-gene mutations, making them good candidates for gene-editing therapy. The method, CRISPR-Cas9, uses DNA sequences from bacteria (clustered regularly interspaced short palindromic repeats, or CRISPR) and a CRISPR-associated enzyme (Cas for short) to edit the patient’s genome. The CRISPR sequences are transcribed onto RNA that locates and identifies DNA sequences to blame for a particular condition. When packaged together with Cas9, transcribed RNA locates the target sequence, and Cas9 snips it out of the DNA, thereby repairing or deactivating the problematic gene.

At a conference this past June, Vertex Pharmaceuticals and CRISPR Therapeutics announced unpublished results from a clinical trial of beta thalassemia and sickle cell patients treated with CTX001, a CRISPR-Cas9-based therapy. In both cases, the therapy does not shut off a target gene but instead delivers a gene that boosts production of healthy fetal hemoglobin—a gene normally turned off shortly after birth. Fifteen people with beta thalassemia were treated with CTX001; after three months or more, all 15 showed rapidly improved hemoglobin levels and no longer required blood transfusions. Seven people with severe sickle cell disease received the same treatment, all of whom showed increased levels of hemoglobin and reported at least three months without severe pain. More than a year later those improvements persisted in five subjects with beta thalassemia and two with sickle cell. The trial is ongoing, and patients are still being enrolled. A Vertex spokesperson says it hopes to enroll 45 patients in all and file for U.S. approval as early as 2022.

Derailing a Potentially Lethal Illness

Spinal muscular atrophy (SMA) is a neurodegenerative disease in which motor neurons—the nerves that control muscle movement and that connect the spinal cord to muscles and organs—degrade, malfunction and die. It is typically diagnosed in infants and toddlers. The underlying cause is a genetic mutation that inhibits production of a protein involved in building and maintaining those motor neurons.

The four types of SMA are ranked by severity and related to how much motor neuron protein a person’s cells can still produce. In the most severe or type I cases, even the most basic functions, such as breathing, sitting and swallowing, prove extremely challenging. Infants diagnosed with type I SMA have historically had a 90 percent mortality rate by one year.

Adrian Krainer, a biochemist at Cold Spring Harbor Laboratory, first grew interested in SMA when he attended a National Institutes of Health workshop in 1999. At the time, Krainer was investigating how RNA mutations cause cancer and genetic diseases when they disrupt a process called splicing, and researchers suspected that a defect in the process might be at the root of SMA. When RNA is transcribed from the DNA template, it needs to be edited or “spliced” into messenger RNA (mRNA) before it can guide protein production. During that editing process, some sequences are cut out (introns), and those that remain (exons) are strung together.

Krainer realized that there were similarities between the defects associated with SMA and one of the mechanisms he had been studying—namely, a mistake that occurs when an important exon is inadvertently lost during RNA splicing. People with SMA were missing one of these crucial gene sequences, called SMN1 .

“If we could figure out why this exon was being skipped and if we could find a solution for that, then presumably this could help all the [SMA] patients,” Krainer says. The solution he and his colleagues hit on, antisense therapy, employs single strands of synthetic nucleotides to deliver genetic instructions directly to cells in the body [see “ The Gene Fix ”]. In SMA’s case, the instructions induce a different motor neuron gene, SMN2 , which normally produces small amounts of the missing motor neuron protein, to produce much more of it and effectively fill in for SMN1 . The first clinical trial to test the approach began in 2010, and by 2016 the FDA approved nusinersen (marketed as Spinraza). Because the therapy does not incorporate itself into the genome, it must be administered every four months to maintain protein production. And it is staggeringly expensive: a single Spinraza treatment costs as much as $750,000 in the first year and $375,000 annually thereafter.

Since 2016, more than 10,000 people have been treated with it worldwide. Although Spinraza can’t restore completely normal motor function (a single motor neuron gene just can’t produce enough protein for that), it can help children with any of the four types of SMA live longer and more active lives. In many cases, Spinraza has improved patients’ motor function, allowing even those with more severe cases to breathe, swallow and sit upright on their own. “The most striking results are in patients who are being treated very shortly after birth, when they have a genetic diagnosis through newborn screening,” Krainer says. “Then, you can actually prevent the onset of the disease—for several years and hopefully forever.”

This article is part of “ Innovations In: Gene Therapy ,” an editorially independent special report that was produced with financial support from Pfizer .

Case Study: Gene Therapy for Enhancement Purposes

Dr. Anderson specializes in a particular type of gene therapy that targets Alzheimer’s Disease (AD).  Neural degeneration and synapse loss in the brain are characteristic of AD.  Therefore, this gene therapy aims to protect neurons from degeneration and enhance the function of any neurons that are remaining. Dr. Anderson has two patients request her services. However, after an initial meeting with them, she is unsure whether she should treat them both.

Alexis is a 50 year-old woman who has a family history of AD and is already beginning to experience very mild symptoms of what she thinks is AD.  She tells Dr. Anderson that her mother was afflicted with AD. So, she knows first-hand the sadness and frustration the family of an AD patient has to experience.  Alexis has a husband and three children and does not want to put them through the same difficult journey. Therefore, she is requesting the gene therapy to reverse the small-scale symptoms she already has and prevent the onset of the disease.

Kelly is a 21 year-old college student who is applying for medical school in the very near future.  Her academic history is strong but not exceptional.  For this reason, Kelly fears that she will not be accepted to the top medical schools. Kelly wants to attend medical school so she can help underserved populations and work in impoverished areas that lack good healthcare. She tells Dr. Anderson that she would like to receive the Alzheimer’s gene therapy in hopes it will boost her memory and enhance neural function.  Kelly believes a good score on the MCAT will strengthen her application and enable her to fulfill her dream of providing medical aid to the world’s neediest people.

Dr. Anderson decides to treat Alexis, as she feels that Alexis is the type of patient that the therapy is designed for.  However, she conflicted about offering the treatment for Kelly.  She doesn’t like the idea of withholding medical treatment from a patient, but the treatment was not originally intended for enhancement purposes.

Should Dr. Anderson treat Kelly?

• Yes. It is not the role of a doctor to make value judgments on who should and should not receive treatment. Ultimately, treating Kelly will benefit mankind when she becomes a doctor
• No. The treatment was designed to help patients that have AD to regain their normal function. Regardless of the reason, gene therapy should not be used for enhancement purposes.

View Results

Gene therapy review: Duchenne muscular dystrophy case study

Affiliations.

• 1 Neurology department, Raymond Poincaré university hospital, AP-HP, Garches, France; Nord-Est-Île-de-France neuromuscular reference center, FHU PHENIX, Garches, France; U 1179 Inserm, université Paris-Saclay, Montigny-Le-Bretonneux, France. Electronic address: [email protected].
• 2 Université Paris Cité, Inserm UMR1163, Imagine Institute, Clinical Bioinformatics laboratory, 75015 Paris, France.
• 3 Neurology department, Raymond Poincaré university hospital, AP-HP, Garches, France; Nord-Est-Île-de-France neuromuscular reference center, FHU PHENIX, Garches, France; U 1179 Inserm, université Paris-Saclay, Montigny-Le-Bretonneux, France.
• 4 Université Paris Cité, Inserm UMR1163, Imagine Institute, Clinical Bioinformatics laboratory, 75015 Paris, France; Genethon, Evry, France.
• PMID: 36517287
• DOI: 10.1016/j.neurol.2022.11.005

Gene therapy, i.e., any therapeutic approach involving the use of genetic material as a drug and more largely altering the transcription or translation of one or more genes, covers a wide range of innovative methods for treating diseases, including neurological disorders. Although they share common principles, the numerous gene therapy approaches differ greatly in their mechanisms of action. They also differ in their maturity for some are already used in clinical practice while others have never been used in humans. The aim of this review is to present the whole range of gene therapy techniques through the example of Duchenne muscular dystrophy (DMD). DMD is a severe myopathy caused by mutations in the dystrophin gene leading to the lack of functional dystrophin protein. It is a disease known to all neurologists and in which almost all gene therapy methods were applied. Here we discuss the mechanisms of gene transfer techniques with or without viral vectors, DNA editing with or without matrix repair and those acting at the RNA level (RNA editing, exon skipping and STOP-codon readthrough). For each method, we present the results obtained in DMD with a particular focus on clinical data. This review aims also to outline the advantages, limitations and risks of gene therapy related to the approach used.

Keywords: DMD; Duchenne muscular dystrophy; Dystrophin; Gene therapy.

Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Publication types

• Dystrophin / genetics
• Dystrophin / metabolism
• Genetic Therapy / methods
• Muscular Dystrophy, Duchenne* / genetics
• Muscular Dystrophy, Duchenne* / metabolism
• Muscular Dystrophy, Duchenne* / therapy

• Gene Therapy

Gene Therapy Case Study: Cystic Fibrosis

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Patient perspectives regarding gene therapy in haemophilia: Interviews from the PAVING study

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5 Institute for Interdisciplinary Innovation in healthcare, Université libre de Bruxelles, Brussels Belgium

Steven Simoens

Isabelle huys, associated data.

The datasets generated for this study will not be made publicly available. Participants did not provide consent for the sharing of interview transcripts with parties other than the researchers.

Introduction

Exploring patient perceptions regarding gene therapies may provide insights about their acceptability to patients.

To investigate opinions of people with haemophilia (PWH) regarding gene therapies. Moreover, this study aimed to identify patient‐relevant attributes (treatment features) that influence PWH’s treatment choices.

Semi‐structured individual interviews were conducted with Belgian PWH, types A and B. A predefined interview guide included information sections and open, attribute ranking and case questions. Qualitative data were organized using NVivo 12 and analysed following framework analysis. Sum totals of scores obtained in the ranking exercise were calculated per attribute.

In total, 20 PWH participated in the interviews. Most participants demonstrated a positive attitude towards gene therapy and were very willing (40%; n = 8) or willing (35%; n = 7) to receive this treatment. The following five attributes were identified as most important to PWH in making their choice: annual bleeding rate, factor level, uncertainty of long‐term risks, impact on daily life, and probability that prophylaxis can be stopped. While participants were concerned about the uncertainty regarding long‐term safety, most participants were less concerned about uncertainty regarding long‐term efficacy.

Conclusions

This qualitative study showed that most PWH have a positive attitude towards gene therapy and that besides efficacy, safety and the related uncertainties, also impact on daily life is important to patients. The identified patient‐relevant attributes may be used by regulators, health technology assessment bodies and payers in their evaluation of gene therapies for haemophilia. Moreover, they may inform clinical trial design, pay‐for‐performance schemes and real‐world evidence studies.

1. INTRODUCTION

Gene therapies are novel treatments that have the potential to generate permanent benefits for patients. For many rare diseases, gene therapies are in development and are increasingly obtaining marketing authorization. However, at the time that market access is sought often uncertainties regarding long‐term efficacy and safety of these therapies remain; reducing the perceived value of these high‐cost treatments. 1 , 2 , 3 , 4

For haemophilia A and B, gene therapies are in late stages of development, but have not yet gained market authorization. These gene therapies come with the promise of a cure for haemophilia where one infusion could possibly replace lifelong administration of other high‐cost treatment options. Current standard of care of severe haemophilia consists of regular invasive intravenous administrations of factor replacement therapy (FRT) that result in fluctuations of achieved factor levels that make people with haemophilia (PWH) more prone to bleeds and joint damage, and may result in development of inhibitors (neutralizing antibodies against exogenous clotting factors) in some PWH. 5 , 6 , 7 , 8

Previous studies investigating attitudes of PWH towards treatment modalities have focused on FRT, blood transfusion, or treatments no longer under development. 9 , 10 Attitudes of PWH towards their current therapy and gene therapy have, to date, only been reported through FDA public patient meetings. 11 and a study of van Balen et al. 12 on patient perspectives regarding multiple novel haemophilia treatments. As gene therapies come with a novel mode of action and uncertainties, gaining a better understanding of patient perceptions regarding these therapies may provide insights about their acceptability to PWH.

This qualitative research aimed to investigate the opinions and concerns of PWH regarding gene therapies. We investigated comprehensibility of information about gene therapies, information needs, willingness to use, and attitudes towards uncertainties. Moreover, this research formed the qualitative phase of the Patient preferences to Assess Value IN Gene therapies (PAVING) study that aims to investigate trade‐offs that adult Belgian PWH make when asked to choose between a standard of care and gene therapy. In preparation of the quantitative phase (survey), this research therefore also aimed to identify patient‐relevant attributes (treatment features).

Interviews and focus group discussions can be used for in‐depth exploration of the patient perspective regarding treatments. 13 , 14 As there was no interest in group dynamics, the choice was made to conduct semi‐structured individual interviews. These interviews were conducted with haemophilia patients from January till June 2019. An advisory board of haematologists, health technology assessment (HTA) and payer decision‐making experts, industry market access experts, rare disease experts, patient education experts and patient representatives was consulted during study design. Details on the methods and results of the interviews were reported according to the guidelines of Hollin et al. 15 and the consolidated criteria for reporting qualitative research (COREQ) checklist was completed (Appendix S1 I) 16 .

2.1. Interview guide development

A predefined interview guide was designed for use in the interviews (Appendix S1 II). Prior to any questions, participants received information regarding the disease, standard of care and gene therapy. Comprehensibility to participants and additional information needs were assessed during the interviews. The content of the information sections and the rest of the interview guide were informed by a systematic literature review that resulted in the identification of 13 clinical trial publications and 19 patient preference studies/public meetings (Appendix S1 III). Moreover, information sections covered aspects highlighted in the work of Miesbach et al, 17 including but not limited to uncertainty in long‐term safety and efficacy, eligibility criteria, variability in achieved outcomes, and current absence of major safety issues. The information sections were followed by open questions to investigate participants’ attitudes towards gene therapy and reasons to refrain from or accept gene therapy.

To date, there is no single guideline stating how attributes should be identified for subsequent quantitative preference research. 18 Our interview guide combined three techniques: 1) open questions to detect new attributes not identified during literature review (bottom‐up) and to question participants about the importance of attributes identified in literature (top‐down), 2) ranking exercises and 3) case questions. 18 , 19 , 20 , 21 Bottom‐up attributes were identified by asking participants about the top three elements that would influence their choice between standard of care and gene therapy before showing any top‐down identified attributes. Literature from the systematic literature review informed the identification of 22 top‐down attributes. Consultation with the advisory board resulted in the exclusion of four top‐down attributes relating to cost and manufacturing. In the end, 18 top‐down attributes were included in the ranking exercise. Participants ranked their top six attributes among the top‐down and bottom‐up identified attributes. Case questions were then asked to confirm the importance of attributes in making choices between gene therapy and other treatment profiles (standard prophylactic FRT, long‐acting FRT or non‐factor replacement therapy; NFT).

The content of the interview guide was validated by three haematologists and piloted with two patient representatives. The interview guide was established in Dutch and translated into English and French by a certified translator; translations were checked by one of the researchers (EvO).

2.2. Participant recruitment

Participants were recruited through purposive sampling to reach heterogeneity in age, type of haemophilia (A/B) and disease severity (moderate/severe). Recruiting parties included the Belgian national haemophilia patient organization (AHVH), and haematologists from Belgian haemophilia reference centres (UZ Leuven and Cliniques Universitaires Saint‐Luc‐UCLouvain). Participants were included if they were 18 years or older, suffered from haemophilia A or B and lived in Belgium.

2.3. Conduct of interviews

Semi‐structured interviews were executed in person and in the native language of the participant (Dutch or French). After informed consent was given, a short demographics and health literacy 20 questionnaire was completed (Appendix S1 IV). The interview guide was used to present information and ask predetermined questions. However, open discussion was also held to explore opinions in‐depth. Interviews were audio‐recorded and transcribed verbatim. All transcripts were produced in the original language and non‐English quotes were only translated into English upon inclusion in the manuscript.

2.4. Analysis

Demographic, clinical and health literacy information, as well as answers to closed, ranking and case questions, were reported using descriptive statistics. Results from the ranking exercise were transformed: for each participant, a score between 1 and 6 was assigned to each of the attributes in their top six, with 6 points being assigned to the most important attribute. Sum totals of the scores were calculated per attribute to generate a list of the ten attributes most important to PWH.

Data from answers to open questions were organized using NVivo 12 and analysed following framework analysis, a type of thematic analysis 22 (Appendix S1 V). Framework analysis was chosen as it allows for a structured analysis of qualitative data by themes. 22 Analysis started with familiarization through the conduct, transcription and reading of interviews. Themes of the interview guide informed the creation of deductive codes. The first 4 transcripts were independently coded by two researchers (EvO and SM) and then compared. Based on observed patterns, inductive codes were created. The inductive and deductive codes together formed a ‘coding tree’ (Appendix S1 VI). The coding tree was uploaded in NVivo and applied to all transcripts, where sections of transcripts relating to a particular theme were classified under the respective code. All data were summarized into a framework matrix. The data of the interviews were interpreted, summarized per code, and some quotes of individual interviewees were added for clarification. Data saturation, meaning that no new topics, opinions or views were gathered in following interviews, was assessed through a saturation table and documented codebook development according to Kerr et al. 14 , 23 (Appendix S1 VII).

3.1. Participant characteristics

First contact was established with 32 PWH of which 20 participated in interviews. Data saturation was reached after inclusion of the first 11 participants (Appendix S1 VII). Most participants were older than 40 years of age (75%) and lived in Flanders (65%) (Table ​ (Table1). 1 ). Most had severe haemophilia (80%), had moderate (45%) to severe (45%) joint damage and were on a prophylactic treatment regimen (75%). All participants were either satisfied or very satisfied with their current treatment. Health literacy was adequate in all participants. Participants that had already discussed treatment with gene therapy with their physician (65%) reached a decision to not receive gene therapy, to receive gene therapy in a clinical trial or no decision was reached.

Participant characteristics (self‐reported).

There was variability in baseline knowledge about gene therapy. While all participants had already heard of gene therapy before the interview, they had very good (5%), good (30%), reasonable (50%) bad (10%) or very bad (5%) self‐reported baseline knowledge about gene therapy. Most participants knew that a virus‐based vector is used to provide a gene to the liver that will allow the liver to produce coagulation factor. Most participants received information about gene therapy through their haematologist (60%), Internet/media (50%) and local patient organization (30%).

3.2. Information about the disease, standard of care and gene therapy

Participants found all provided information about haemophilia, standard of care and gene therapy comprehensible. Additional information about the following topics was requested by multiple participants: inhibitors against FRT, durability and magnitude of achieved factor level, number of years evidence has been gathered, number of PWH treated, the concept of viral vectors, the difference between inhibitors and antibodies against the vector, (long‐term) side effects, development of light inflammation of the liver, duration and side effects of treatment with corticosteroids, follow‐up and restrictions after gene therapy administration, alternative treatment if benefits are not maintained in the long‐term (re‐administration of gene therapy or re‐use of FRT), as well as cost and reimbursement. Moreover, several participants suggested using examples and illustrations to visualize difficult concepts and ensure comprehension by other PWH.

3.3. Willingness to use gene therapy

Most participants (65%) had a positive attitude towards gene therapy, were surprised by this medical advancement and thought it would greatly impact many PWH lives. Some participants thought the most benefit could be gained in younger PWH as gene therapy could protect them against joint damage and could have a positive effect on their personal and professional lives. Some participants said that gene therapy is still novel and that more evidence is needed regarding efficacy and safety. Others mentioned that it could lead to societal savings and could be a solution for third world countries. When participants were asked if they would be willing to receive treatment with gene therapy, 40% (n = 8) of participants was ‘very willing’, 35% (n = 7) was ‘willing’, 10% (n = 2) was ‘neutral’ and 15% (n = 3) was ‘not willing’. Reasons for using gene therapy were as follows: stable factor level resulting in less risk and number of bleeds, no need for injections, less practical requirements and possibility of travelling, age (more benefit for young PWH and older ones that have lost self‐administration autonomy), and societal cost savings as one administration of gene therapy could potentially replace recurrent administration of current high‐cost FRT. Especially, the number of bleeds seemed to be of substantial importance to participants as ‘it are the bleeds that cause the consequences of your hemophilia’ (PA_7). Reasons to refrain from using gene therapy included: satisfaction with current therapy and PWH ‘don't want to take an unnecessary risk’ (PA_19), uncertainty regarding long‐term safety of gene therapy, loss of haemophilia identity and advantages (invalidity allowance and protection against cardiovascular disease) that was perceived as “scary” (PA_18), intense initial follow‐up, old age and the potential high cost of gene therapy. Most participants found the light liver inflammation provoked by gene therapy administration not to be disturbing if temporary and treatable with corticosteroids, while two others were concerned about the inflammation due to past liver problems (hepatitis C infection). Participants willing to use gene therapy were on average older (54y) and had more severe joint damage (moderate to severe) than participants that would refrain from it (23.5y; mild to moderate joint damage).

3.4. Perception of uncertainties related to gene therapies

Many participants (n = 8) found it ‘logic’ (PA_4) that gene therapy comes with uncertainty regarding long‐term outcomes as it is a novel therapy. Nevertheless, uncertainty regarding long‐term safety of gene therapy was a concern to many participants. In contrast, uncertainty regarding long‐term efficacy was less perceived as an issue by participants as they would already appreciate short periods of efficacy to have a break from FRT administrations and knew they could fall back on FRT if necessary. Five participants required a minimum efficacy duration, from 1 year, to 2, 5 and 20 years. Five other participants expressed some concern regarding the uncertainty in long‐term efficacy. Three participants mentioned that variability in achieved factor level between PWH treated with gene therapy was an important aspect influencing their decision‐making, while others considered small increases in factor level (e.g. 5%) already to be beneficial.

When it was mentioned that a second administration of gene therapy (in case efficacy is not maintained) is currently not possible due to development of antibodies, most participants responded in a neutral manner and did not perceive this as a problem and would switch back to the FRT if necessary. However, three participants found this to be a risk and wondered whether it would be better to wait until better vectors are developed.

3.5. Attribute ranking

From the bottom‐up identified attributes, the attributes mentioned by multiple participants included treatment administration (chance of stopping, mode and frequency; 50%), impact of practical requirements on daily life and travel (40%), bleeding rate (30%), uncertainties (30%), cost (20%) and factor level (variability and stability; 20%). The ranking exercise with top‐down and bottom‐up identified attributes revealed that the five attributes most important to PWH are as follows: annual bleeding rate (ABR), factor level, uncertainty of long‐term risks, impact on daily life and probability that prophylaxis can be stopped (Table ​ (Table2). 2 ). A participant mentioned that while ABR and factor level are both important, they are related and that annual bleeding rate as a clinical result is more important; ‘The two are linked . It is the consequence of the treatment that is most important’ (PA_13) . Attributes found unimportant by PWH mostly included attributes related to administration (e.g. dosage, duration, place, ease, and route of administration; n = 13) and follow‐up/monitoring (n = 7).

Top 10 attributes important to patients.

3.6. Attributes in cases

Hypothetical cases were presented to participants comparing gene therapy to standard prophylactic FRT, long‐acting FRT or NFT. Attributes that were mentioned across cases by multiple participants include annual bleeding rate, factor level, chance of stopping prophylaxis, risk of light liver inflammation (not feared by most), risk of inhibitor development, uncertainty regarding side effects and impact on daily life and travel (Appendix S1 VIII).

4. DISCUSSION

Through interviews with PWH, we were able to gain insights into their willingness to receive gene therapy as well as attributes that influence their choice. Most participants demonstrated a positive attitude towards gene therapy and were very willing or willing to receive treatment with gene therapy. Participants perceived the benefits of gene therapy to be the greatest for younger PWH. However, our study showed that younger PWH may be more reluctant towards gene therapy. This might be a result of current treatment satisfaction with limited joint damage, as also mentioned during the FDA patient meeting 11 .

Five attributes most important to PWH were identified in the ranking exercise: ABR, factor level, uncertainty of long‐term risks, impact on daily life, and probability that prophylaxis can be stopped. These attributes were also mentioned in response to the open and case questions. In the study of van Balen et al. 12 similar factors were identified: ‘Ease of use of the medication’ (including probability that prophylaxis can be stopped), ‘Equally good or better bleed prevention’ (ABR) and ‘Fear of the unknown’ (uncertainty of long‐term risks). The importance of the factor ‘Do not want to be a guinea pig/research subject’ as identified by van Balen et al. 12 was not confirmed in the current study; this difference may be explained by the dissimilar focus of the two studies as the current study focused on use of gene therapy outside the clinical trial setting and the study of van Balen et al. 12 focused on willingness to participate in research and covered multiple novel treatments. Other attributes frequently mentioned in interviews of the current study were variability in achieved factor level, uncertainty in long‐term efficacy and development of light inflammation. However, most participants perceived these uncertainties and risks to be manageable. Many of the concerns reported in the current study were also highlighted in the recent paper of Pierce et al, 24 including eligibility, variability in achieve factor level, durability of expression, quality of life, redosing and impact of liver inflammation. Concerns regarding long‐term safety and efficacy of gene therapy were also mentioned by PWH in the FDA patient meeting. 11 Overall, efficacy (including uncertainties), safety (including uncertainties) and quality of life appear to form the pillars of therapeutic value of gene therapy to PWH (Figure ​ (Figure1). 1 ). Besides therapeutic value, this study showed that PWH also want to limit the burden on society caused by societal costs of their current therapy and gene therapy; confirming similar results of van Balen et al. 12 However, opposite beliefs were identified on the cost‐saving potential of gene therapy.

Pillars of gene therapy therapeutic value to patients.

Results of this study confirm the importance of certain outcomes included in the coreHEM core outcomes set for gene therapy in haemophilia identified through a multi‐stakeholder project by Iorio et al, 25 namely bleeding rate, factor level and duration of efficacy. However, the importance of chronic pain, healthcare resource use after gene therapy administration and mental health were not confirmed. While pain and mental health may be important to PWH, the researchers believe that participants in the current study may have perceived prioritized attributes to be proxies for these non‐prioritized attributes. Other differences may be explained by the difference in consulted stakeholders and the difference in decision context; the coreHEM initiative aimed to identify outcomes for gene therapy unrelated to any other treatment while the current study investigates how PWH make choices between gene therapy and standard of care.

4.1. Strengths and limitations

While qualitative research allows for the exploration of thoughts and opinions and cannot ensure objectivity, validity of the study was ensured through validation of the interview guide by clinical experts and patient representatives, pilot interviews and assessment of data saturation. While identification of attributes was carried out via a systematic search, measures taken in haemophilia gene therapy clinical trials that may impact lifestyle (e.g. reduction of alcohol consumption and use of contraception to prevent sexual transmission of the vector) were not included in the list of top‐down identified attributes as at the time of the study it was uncertain if these measures should also be taken when gene therapy is administered outside clinical trials once the therapy is approved. Results of this qualitative research were transparently reported according to the guidelines of Hollin et al 15 and the COREQ checklist. 16 Moreover, triangulation of patient‐relevant attributes was achieved by employing three approaches to identify these: open, ranking and case questions.

Participants were recruited via the national patient organization and two hospitals. The study had a high response rate (62.5%). While the researchers aimed to include a heterogeneous sample of PWH (in terms of severity, residence and other demographics, and prior knowledge), it is uncertain if interest in gene therapy may have resulted in sampling bias. Health literacy was adequate in all participants, but substantial variability was observed in baseline knowledge about gene therapy. The researchers aimed to correct this variability by educating participants about gene therapy. However, differences in baseline knowledge may still have influenced responses.

To ensure information on gene therapy was objectively presented to participants and to minimize the variability between interviews, only two researchers (EvO and SM) conducted the interviews and they were both trained on the topic. SM conducted the interviews with Dutch‐speaking participants and EvO the interviews with French‐speaking participants. EvO supervised the conduct of the first three interviews by SM to ensure interviews were performed in the same manner by the two interviewers in the two languages. Both interviewers were trained on the topic of gene therapy in haemophilia by attending seminars given on the topic by experts in the field, conducting the literature review that informed the interview guide, and discussing the content of the interview guide with three haematologists and two patient representatives. Furthermore, the clinical information provided to participants in interviews was predefined in the interview guide and validated by three haematologists, and the interviewers did not deviate from this script.

While a large amount of often new information was provided to PWH, the interviewers made sure to go through the information and questions at the pace comfortable for the participant to prevent participants from feeling overwhelmed. Moreover, after every information section participants were asked whether they understood the information and all participants found these sections comprehensible. It could be possible that some bias in responses to these comprehension questions occurred as participants may not have wanted to admit that they did not understand the information. However, many participants asked additional questions about the information provided; showing that they felt comfortable expressing their additional information needs.

This research was performed with a small sample, in which PWH type B and PWH between 26 and 40 years old were underrepresented. Therefore, the results are likely not representative of the entire Belgian haemophilia population. However, a quantitative preference study (survey) will be designed based on the findings of the interviews reported in this paper to obtain more representative results in a larger sample of PWH. For this quantitative study, we aim to include a sample representative of the gene therapy target population. Results from this quantitative phase may provide more insights regarding the relative importance of attributes, acceptance of gene therapy to the full population, and influence of patient characteristics on acceptance; such as age and joint damage as preliminary identified in the current study.

4.2. Implications and future use

This qualitative study identified attributes important to PWH which may be used by regulators, HTA bodies and payers in their evaluation of gene therapy for haemophilia. 26 , 27 , 28 , 29 The identified attributes represent patient‐relevant outcomes and needs of PWH which may inform HTA in the identification of gene therapy clinical trials reaching patient‐relevant endpoints and studies investigating quality of life. The patient‐relevant outcomes identified in the current study may also be included in pay‐for‐performance schemes of managed‐entry agreements. Additionally, the concerns of PWH about uncertainty of long‐term safety and efficacy may inform future real‐world evidence studies.

5. CONCLUSIONS

Most PWH have a positive attitude towards gene therapy. Their willingness to receive gene therapy is predominantly motivated by the promise of a reduction in bleeds, high and stable factor level, potential impact on daily life and chance of stopping prophylactic FRT. However, PWH also recognize the uncertainties that gene therapies come with and are more concerned about uncertainty regarding long‐term safety than long‐term efficacy. Regulators, HTA bodies and payers can use the patient‐relevant attributes identified in this study to support gene therapy evaluations in haemophilia.

6. ETHICS STATEMENT

All interviewees provided written informed consent prior to starting the interview. Ethical approval was obtained from the Medical Ethics Committee of UZ KU Leuven/Research in Belgium ( {"type":"entrez-protein","attrs":{"text":"S62670","term_id":"2143728","term_text":"pir||S62670"}} S62670 ).

CONFLICT OF INTEREST

The authors have no competing interests to declare.

AUTHOR CONTRIBUTIONS

EvO, SM, BH, KP, CH, CL, MG, SS and IH were involved in the design of the study. EvO and SM designed study materials, held interviews with patients and analysed results. BH, KP, CH, CL, MG, SS and IH participated in meetings and reviewed study materials. EvO produced the first draft of the manuscript, which was subsequently revised and finalized with all authors. All authors approved the final manuscript.

Supporting information

Appendix S1

ACKNOWLEDGEMENTS

The authors would like to thank Nigel Cook (Novartis), Juhaeri Juhaeri (Sanofi), Ami Patel (CSL Behring) and the other members of the extended team for their review of the protocol, and all members of the PREFER project for their support in the development of this protocol. In addition, we thank Guildhawk for their translations of the interview guides. Special thanks to Nancy Thiry (Belgian Health Care Knowledge Centre, KCE), Irina Cleemput (KCE), Wim Goettsch (National Health Care Institute/University of Utrecht), Rene Westhovens (UZ Leuven), Patrick De Smet (the Belgian haemophilia association, AHVH), Noémie Colasuonno (AHVH), Mitchell Silva (the Belgian European Patients Academy on Therapeutic Innovation, EUPATI BE), and the other members of the advisory board for their support of this study.

Funding information This study was funded by the Patient Preferences in Benefit‐Risk Assessments during the Drug Life Cycle (PREFER) project. The PREFER project has received funding from the Innovative Medicines Initiative (IMI) 2 Joint Undertaking under grant agreement No 115966. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This text and its contents reflect the PREFER project's view and not the view of IMI, the European Union or EFPIA.

DATA AVAILABILITY STATEMENT