case study on 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

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

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).

Training the Immune System to Fight Cancer

“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.

Precision Editing for Blood Disorders

Derailing a Potentially Lethal Illness

“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.

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

Gene Therapy

Explore the what's and why's of gene therapy research, includingan in-depth look at the genetic disorder cystic fibrosis and how gene therapy could potentially be used to treat it.

Explore the methods for delivering genes into cells.

You are the doctor! Design and test gene therapy treatments with ailing aliens.

Researchers hoping to bring gene therapy to the clinic face unique challenges.

Beyond adding a working copy of a broken gene, gene therapy can also repair or eliminate broken genes.

The future of gene therapy is bright. Learn about some of its most encouraging success stories.

Supported by a Science Education Partnership Award (SEPA) Grant No. R25RR023288 from the National Center for Research Resources.

The contents provided here are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

Case Study: Gene Therapy for Enhancement Purposes

Dr. Anderson specializes in a particular type of gene therapy that targets Alzheimerâ€™s Disease (AD). Â Neural degeneration and synapse loss in the brain are characteristic of AD.Â Therefore, this gene therapy aims to protect neurons from degeneration and enhance the function of any neurons that are remaining.Â 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.Â 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.Â 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.Â Her academic history is strong but not exceptional.Â 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 Alzheimerâ€™s gene therapy in hopes it will boost her memory and enhance neural function.Â 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 worldâ€™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.Â However, she conflicted about offering the treatment for Kelly.Â She doesnâ€™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.

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Addressing the dark matter of gene therapy: technical and ethical barriers to clinical application

Published: 08 April 2021
Volume 141 , pages 1175–1193, ( 2022 )

Cite this article

Kateryna Kratzer ORCID: orcid.org/0000-0003-0215-9974 1 na1 ,
Landon J. Getz ORCID: orcid.org/0000-0002-3841-1062 2 na1 ,
Thibaut Peterlini 3 , 4 ,
Jean-Yves Masson ORCID: orcid.org/0000-0002-4403-7169 3 , 4 &
Graham Dellaire ORCID: orcid.org/0000-0002-3466-6316 1 , 2 , 5

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Gene therapies for genetic diseases have been sought for decades, and the relatively recent development of the CRISPR/Cas9 gene-editing system has encouraged a new wave of interest in the field. There have nonetheless been significant setbacks to gene therapy, including unintended biological consequences, ethical scandals, and death. The major focus of research has been on technological problems such as delivery, potential immune responses, and both on and off-target effects in an effort to avoid negative clinical outcomes. While the field has concentrated on how we can better achieve gene therapies and gene editing techniques, there has been less focus on when and why we should use such technology. Here we combine discussion of both the technical and ethical barriers to the widespread clinical application of gene therapy and gene editing, providing a resource for gene therapy experts and novices alike. We discuss ethical problems and solutions, using cystic fibrosis and beta-thalassemia as case studies where gene therapy might be suitable, and provide examples of situations where human germline gene editing may be ethically permissible. Using such examples, we propose criteria to guide researchers and clinicians in deciding whether or not to pursue gene therapy as a treatment. Finally, we summarize how current progress in the field adheres to principles of biomedical ethics and highlight how this approach might fall short of ethical rigour using examples in the bioethics literature. Ultimately by addressing both the technical and ethical aspects of gene therapy and editing, new frameworks can be developed for the fair application of these potentially life-saving treatments.

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Acknowledgements

We gratefully acknowledge feedback during the preparation of this review from Sabateeshan Mathavarajah and Dr. Françoise Baylis.

K.K. is a trainee of the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Dalhousie Medical Research Foundation (DMRF) C. MacDougall Cancer Research Studentship, as well as being supported by a Genomics in Medicine Graduate Studentship from the Dalhousie Faculty of Medicine –DMRF and a Nova Scotia Scholar Award. L.J.G. is funded by a Vanier Canadian Graduate Scholarship from the Natural Science and Engineering Research Council of Canada (NSERC) as well as a Killam Pre-Doctoral Scholarship from the Killam Trusts. J-Y.M. is a Canada Research Chair in DNA repair and Cancer Therapeutics. This work is also supported by a Canadian Institutes of Health Research (CIHR) Project Grant (PJT-156017) to J-Y.M. and G.D.

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Kateryna Kratzer and Landon J. Getz contributed equally to the work.

Authors and Affiliations

Department of Pathology, Faculty of Medicine, Dalhousie University, PO BOX 15000, Halifax, NS, B3H 4R2, Canada

Kateryna Kratzer & Graham Dellaire

Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, PO BOX 15000, Halifax, NS, B3H 4R2, Canada

Landon J. Getz & Graham Dellaire

Genome Stability Laboratory, Oncology Division, CHU de Québec Research Centre, Quebec, Canada

Thibaut Peterlini & Jean-Yves Masson

Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, 9 McMahon, Quebec, G1R 3S3, Canada

Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada

Graham Dellaire

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KK and GD conceived of the review. KK, LG and GD generated Figs. 1 and 3 , and J-YM and TP generated Figs. 2 and 4 . All authors contributed to the writing and edited of the manuscript.

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Kratzer, K., Getz, L.J., Peterlini, T. et al. Addressing the dark matter of gene therapy: technical and ethical barriers to clinical application. Hum Genet 141 , 1175–1193 (2022). https://doi.org/10.1007/s00439-021-02272-5

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DOI : https://doi.org/10.1007/s00439-021-02272-5

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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.

Publication types

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

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SCID – also known as severe combined immunodeficiency – is a very rare genetic disorder which only affects between 1 in 50,000 and 1 in 100,000 births. Children born with SCID do not have an effective immune system , so they are extremely vulnerable to any form of infection. In many instances, all of the problems result from a single defective gene coding for the enzyme adenosine deaminase. Boys are more often affected than girls because at least one form of the disease is sex-linked (carried on the X chromosome ).

In the past, the only way of keeping these children alive was to bring them up in a completely sterile environment, with all their food, water and air sterilised and with no direct contact with other people. Even then, affected children rarely lived into their teens as the slightest contamination could kill them.

Another alternative is a bone marrow transplant if a suitable donor can be found. Although the affected child has no immune system to cause rejection , the transplanted marrow can attack the patient’s cells. What is more, the donor cells may be infected with a virus – and this can kill the recipient very quickly. Patients can also be regularly injected with the enzyme they need, but this involves a lifetime of carefully managed therapy.

Life for children with SCID without treatment is very limited.

So gene therapy , inserting a healthy gene into the DNA using a vector such as a specially modified virus, offers the exciting possibility of a normal life for children who otherwise have a limited life expectancy and relatively poor quality of life.

The first ever attempts at gene therapy were carried out on children with SCID. Different variations of the technique were tried on children in several countries, including Britain. The trials had considerable success – the children treated all developed functioning immune system s which enabled them to fight off infections and to make antibodies when they were given vaccines. They could leave hospital, and their sterile environments, and live normal lives.

Then came the news that, about 3 years after their treatment, first one and then two of the nine children with SCID treated successfully using gene therapy in France developed leukaemia -like symptoms. They responded well to chemotherapy , but both the French and the American governments halted trials of gene therapy for SCID until more was known about why these boys fell ill and whether it was linked to the gene therapy.

The UK government decided differently, feeling that the potential benefits outweighed the possible risks. This view was backed up both by doctors carrying out the therapy at Great Ormond Street Hospital and by the mother of Rhys Evans, the first British boy to be given gene therapy. He received the treatment in 2001, when he was an infant, and he is now a healthy young man, enjoying normal life with a functioning immune system. Great Ormond Street has had many success stories treating this extremely rare condition with gene therapy. They are now considering ways to use the same techniques to tackle other genetic diseases.

Professor Nevin, who chaired the UK committee which made the decision that work should continue commented: "As with all innovative treatments, there will always be the potential for side-effects."

Dr Bobby Gaspar of Great Ormond Street Hospital said: "If we stop these studies now we will be denying extremely effective therapy to children and they may suffer as a result of not receiving this therapy. Ethically we believe it is the right thing to go on."

Marie Evans, the mother of Rhys who has undergone the treatment, also had an opinion.

"If they stop something just because one child has an adverse effect at the end of the day medicine and the world just doesn't go on," she said.

Gene therapy isn’t suitable for all patients, but at Great Ormond Street a number of children have now been successfully treated, without developing leukaemia, and trials into other uses of the technology are underway.

Sickle cell disease

Sickled red blood cells do not carry oxygen effectively and they block small blood vessels. Gene therapy holds out the hope of dealing with both problems in one solution.

Unlike SCID, which is extremely rare, sickle cell disease affects millions of people around the world. In sickle cell disease, a mutation in a single gene affects the formation of one of the two types of protein chain which make up haemoglobin . This changes the shape of the haemoglobin molecule and reduces its ability to carry oxygen. The mutated haemoglobin also makes the red blood cells take on a sickle shape instead of the normal biconcave discs. These sickled red blood cells tend to stick together. They block small blood vessels , causing terrible pain and often tissue damage as well. People who are affected need regular blood transfusions, and often strong painkillers. Bone marrow transplant s can treat the disease, but only about 10% of the millions of people affected globally ever find a matching donor. Ultimately - and especially if untreated – sickle cell disease can kill.

In 2017 French scientists announced that they had reversed the progress of sickle cell disease in a teenage boy, by genetic modification of his bone marrow. The boy was very severely affected. By 13 he had had his spleen removed and his hips replaced, and he needed opioid painkillers to deal with the pain. Scientists took bone marrow stem cell s, genetically modified them using a viral vector so they could make functioning haemoglobin, and replaced the stem cells in the patient. For 15 months the boy has been making normal haemoglobin, and his red blood cells have functioned perfectly normally. He does not need transfusions or painkillers.

Scientists are always wary of claiming to have found a cure – and this patient is the first to succeed in the clinical trials. It will require many more years of testing – and success in other patients – before the procedure can be declared a complete success but this appears to be a major step forward. Seven other patients have been treated by the French team and they are also showing promising progress.

This is a very exciting development which could potentially help huge numbers of people – for example, 100,000 people are affected by sickle cell disease in the US alone. However, it also raises some ethical questions. The majority of people affected by sickle cell disease live in relatively poor countries, with limited health infrastructure. They do not have the resources to offer gene therapy to everyone – or even a minority – of the people affected. So at the moment, even if gene therapy does provide a cure for sickle cell disease, it will be a cure which is only available to affected people in the richer countries of the world. Perhaps as gene editing becomes more common and more successful it will become easier and cheaper and therefore available globally.

Perhaps we will need to find other ways of treating this and other genetic diseases. Whatever the future holds, we need to consider both the science and the ethics of the treatments we develop.

You can find out more about SCID and the use of gene therapy here: Treating the bubble babies: gene therapy in use, Your Genome Severe combined immunodeficiency , Great Ormond Street Hospital for Children Gene therapy success, Great Ormond Street Hospital for Children

Find out more about gene therapy and sickle cell disease here: Gene therapy ‘cures’ boy of blood disease that affects millions, New Scientist Teenager’s sickle cell reversed with world-first therapy, BBC News website

Muscular dystrophy – the importance of animal models

Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy. It affects about one in every 3500 boys who are born – about 100 boys a year in the UK. It is a sex-linked genetic condition which means the boys cannot make a protein called dystrophin, a protein vitally important for maintaining healthy muscles. Without it the muscles weaken and waste away, being replaced by fat, so that by their early teens most affected boys are confined to a wheelchair and their life expectancy is only to early adulthood.

The faulty gene is very large, which makes normal gene therapy techniques difficult. However researchers in the United States and in Britain have found ways of using parts of a healthy gene, called mini-genes, to repair the damaged DNA, enabling the muscles to produce dystrophin and to function in a much more normal way. What is more, the effect has been long term – the protein was still being made a year after the gene was inserted. The only problem is that the gene therapy technique has so far only been tried in mice and golden retrievers, which have a natural mutation similar to muscular dystrophy .

Much of this research depends on knockout mice. To produce knockout mice researchers genetically modify some embryo nic stem cell s to inactivate or ‘knock out’ a healthy gene. These cells are then injected into mouse embryos which are then implanted into a surrogate mother. The mice which result have some knockout cells and some normal cells, and they are then implanted to produce homozygous knockout mice.

Knockout mice often show changes in their phenotype which mimic human genetic problems , helping scientists understand exactly what the gene does.

Knockout mice are also useful for studying the impact of different therapies. We have many of our genes in common – of 4000 genes studied in mice and humans, only ten of them are found in one species but not in the other. This, along with the fact that mice reproduce rapidly, have large litters, and are easy and cheap to keep means that knockout mice are incredibly useful in our search to understand gene functions and to find cures for many diseases.

The problem with the mdx mice (a popular model for studying DMD) is that they only display relatively mild symptoms. Several breeds of domestic dog have also been found to have a natural mutation in the dystrophin gene and some work has been done on golden retrievers. Dogs are not ideal laboratory animals for many reasons – they are intelligent and emotive, they are not easy to manipulate genetically, and they take time and effort to breed. However, dogs affected by the canine form of Duchenne muscular dystrophy do have symptoms which are very similar to humans. Now a team at the Royal Veterinary College have discovered a line of King Charles spaniels which appear to have the same mutation in the same gene as humans. A research project began in 2015 looking at the progression of the disease in this breed of dog. This may in future lead to improved therapies for humans and dogs alike.

Many of the current trials on possible treatments for DMD still involve the use of medicines to alleviate symptoms, but there have been some promising results recently with genetic modification in both mice and dogs. A few phase 1 human clinical trials are in progress and more are expected soon. Some scientists are attempting to replace small regions of the faulty gene, others are trying to replace the whole thing. Gene therapy has not yet been fully successful in overcoming any genetic diseases, so any patients who take part in early trials of a possible new treatment – and their parents – are very brave. New technologies such as CRISPR-Cas9 hold out hope for new therapies including editing muscle-forming stem cell s rather than trying to change the whole organism. There is a long way to go, but muscular dystrophy is another disease where gene therapy may eventually result in a treatment or even a cure.

See: Knockout Mice Fact Sheet, National Human Genome Research Institute Why Mouse Matters, 2000 Mouse Sequencing Consortium, National Human Genome Research Institute A new animal model of Duchenne muscular dystrophy, Muscular Dystrophy UK

Discussion Point

Animals are frequently used in scientific research.

What are some arguments for and against this?

Transgenic plants – food for the future

Gene silencing.

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Case Study on Gene Therapy

Gene therapy case study:.

Gene therapy is the complex of the genetic and medical methods, which are aimed at the change of the genes of a patient’s cells in order to cure a disease. Gene therapy is becoming more and more popular, because there are many diseases which are caused by mutations of genes, so the therapy is often the only way out to cure such a disease. The development of gene therapy started in the end of 1980 with the invention of the equipment, which can conduct scrupulous operations. At first gene therapy was planned to treat genetic diseases, which can not be cured in other way.

Nevertheless, the scope of the method developed much further and other diseases started to be treated with the help of the therapy. There are two main types of gene therapy, which differ according to their consequences and further impact on the organism of a patient.The first type is the somatic gene therapy. The principle of this kind of therapy is the introduction of the therapeutic genes into the organism but they do not change the genetic code and are active during the life of the patient. That means, a child of the patient will not inherit the acquired modifications, so somatic gene therapy is considered to be quite a safe process.

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The second type is the germ line gene therapy. According to this kind of therapy genes are introduced into the germ cells (eggs, sperm), what means that the modification will be inherited by the offspring and his later generations.Gene therapy is considered to be one of the most effective ways to cope with some genetic diseases, so students should be aware of the key aspects of the therapy in order to be professionals in their sphere. Evidently, before writing the case study one should read a lot to improve the general background knowledge on the topic to be able to analyze it soberly and provide the teacher with wise conclusions. Then, researching the problem for a case study one should collect enough trustworthy data from the high-quality sources, like the articles written by the professional scientists, articles based on the interviews with the patients, etc.

Students are supposed to prepare an interesting and informative piece of writing on the definite topic based on gene therapy. The main problem which disappoints students is not the process of the analysis and research but the process of the organization of the paper. A free example case study on gene therapy is quite an effective help for students who have difficulties with paper writing. Sometimes one requires a free sample case study on gene therapy to be able to create the appropriate structure for the logical organization of the text and format the paper well.

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

Eline van overbeeke.

1 Clinical Pharmacology and Pharmacotherapy, University of Leuven, Leuven Belgium

Sissel Michelsen

Brett hauber.

2 Health Preference Assessment, RTI Health Solutions, Research Triangle Park NC, USA

Kathelijne Peerlinck

3 Haemophilia Center, UZ Leuven, Leuven Belgium

Cedric Hermans

4 Haemophilia Clinic, St‐Luc University Hospital, Brussels Belgium

Catherine Lambert

Michel goldman.

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.

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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.

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

Sissel Michelsen

Kathelijne Peerlinck

Cedric Hermans

Catherine Lambert

Steven Simoens

Introduction

Conclusions

1. INTRODUCTION

2.1. Interview guide development

2.2. Participant recruitment

2.3. Conduct of interviews

2.4. Analysis

3.1. Participant characteristics

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

3.3. Willingness to use gene therapy

3.4. Perception of uncertainties related to gene therapies

3.5. Attribute ranking

3.6. Attributes in cases

4. DISCUSSION

4.1. Strengths and limitations

4.2. Implications and future use

5. CONCLUSIONS

6. ETHICS STATEMENT

CONFLICT OF INTEREST

AUTHOR CONTRIBUTIONS

Supporting information

ACKNOWLEDGEMENTS

DATA AVAILABILITY STATEMENT

IMAGES

VIDEO

COMMENTS