Gene therapy for Duchenne muscular dystrophy
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Gene therapy is a treatment strategy for Duchenne muscular dystrophy (DMD) designed to target the underlying cause of the genetic disorder. There is no cure for DMD; gene therapy aims to help slow or stop the progression of the disease so patients can retain better motor function for longer.
DMD is caused by mutations in the gene DMD, which provides instructions for making the protein dystrophin. That protein normally functions like a shock absorber of sorts in muscle cells, protecting them from damage during movements. Without a working version of dystrophin, muscles accumulate more wear and tear damage over time, which ultimately leads to disease symptoms that include progressive muscle weakness.
What is gene therapy?
The overarching goal of gene therapy for DMD is to deliver new genes into muscle cells that can work to support muscle health, thereby slowing disease progression.
The approved gene therapy Elevidys, as well as several experimental gene therapies, aim to provide a working version of the DMD gene that can allow muscle cells to produce a functional version of dystrophin. Other gene therapies in development are designed to deliver to cells other genes that may help protect muscles from the damage driving DMD symptoms.
Most gene therapies work using a viral vector. Viruses have evolved to be good at getting into cells, so they are a good platform to deliver therapeutic genes.
In gene therapies for DMD, viruses are typically engineered to deliver therapeutic genes to muscle cells, which are most affected by the disease. A particular type of virus, called adeno-associated virus (AAV), has been used in many gene therapies because it doesn’t normally cause disease in people and it’s relatively easy to engineer for therapeutic use.
Elevidys
Elevidys (delandistrogene moxeparvovec-rokl), previously known as SRP-9001, is the only approved gene therapy for DMD. It uses an AAV-based vector to deliver to muscle cells a gene encoding micro-dystrophin, which is a shortened but functional version of the dystrophin protein.
The U.S. Food and Drug Administration (FDA) granted accelerated approval to Elevidys in June 2023 as a treatment for boys with DMD, ages 4 to 5, who are able to walk. Under the accelerated approval pathway, the FDA can authorize a therapy for use based on positive biomarker data from early clinical trials.
Elevidys, marketed by Sarepta Therapeutics, was approved based on early data showing it can increase the production of micro-dystrophin in muscle cells as designed. The FDA determined these data indicate the therapy is reasonably likely to provide a benefit for patients.
Early clinical trial data have generally suggested that boys given Elevidys tend to have better motor function than might be expected without treatment, but studies still are ongoing to confirm if and how much this DMD therapy may alter disease progression.
Experimental gene therapies
Several experimental gene therapies for DMD are now in clinical development.
- PF-06939926 (fordadistrogene movaparvovec), designed to deliver a gene encoding a short but functional version of the dystrophin protein (or mini-dystrophin), is being developed by Pfizer. Early trial data suggested the therapy was safe and appeared to improve motor function; further studies are ongoing.
- SGT-001, being developed by Solid Biosciences, is designed to deliver to muscle cells a gene encoding a shortened dystrophin called microdystrophin. Early data have suggested it may improve motor function, but clinical studies are still ongoing.
- GALGT2, designed to deliver the muscle gene GALGT2, is being developed by Sarepta in collaboration with Nationwide Children’s Hospital. An early clinical trial in two boys with DMD suggested it was well tolerated and helped stabilize muscle function when delivered at a higher dose.
Can gene therapy treat DMD?
Gene therapies are designed with the aim of slowing or stopping the progression of DMD, which would allow patients to maintain better motor function for longer.
Early clinical data suggest children with DMD who are given gene therapy may retain better motor function compared with what’s typically seen without such treatment. However, because gene therapies only recently have entered into clinical testing, the extent of their therapeutic benefits overall remain largely unknown.
Elevidys, the only gene therapy approved to date for DMD, was granted accelerated approval based on biomarker data suggesting it can increase dystrophin production as designed. Sarepta’s therapy provides cells with instructions to produce an Elevidys micro-dystrophin.
The DMD gene is the longest in the human genome, which has represented a challenge in designing gene therapies that can be packaged inside a delivery vehicle. As such, scientists have been exploring trimmed-down, working versions of dystrophin.
Clinical trials to definitively evaluate whether and how much Elevidys affects disease progression are still ongoing.
While gene therapies may slow or stop DMD from worsening, it’s unclear if they might help patients regain functionality that’s already been lost. As such, the effects of gene therapy are expected to vary substantially depending on when treatment is given — generally, the best outcomes are expected when treatment is given early in the course of the disease. Initial clinical trials of Elevidys have focused on young children who are still able to walk, but testing the therapy in broader ranges of patients is ongoing.
Potential risks and issues
As with any medical treatment, there are potential risks and side effects associated with gene therapy.
Elevidys, the only currently approved gene therapy for DMD, can cause complications including liver injury, heart inflammation, and muscle inflammation. Monitoring is required in the weeks after treatment to manage these risks.
Other common side effects of Elevidys include:
- nausea and vomiting
- fever
- low levels of platelets.
Immune-mediated myositis
The immune system is responsible for defending the body against infectious invaders — but it also can cause problems with DMD gene therapies.
In some patients treated with gene therapies like Elevidys that deliver a version of the dystrophin protein, the immune system mistakes the new protein for a threat and launches an inflammatory attack that damages the body’s own muscles. This reaction, known as immune-mediated myositis, is characterized by symptoms like muscle pain and weakness; it can be severe or life-threatening in some patients.
While risk factors for immune-mediated myositis are incompletely understood, available data suggest patients with certain mutations in the DMD gene are more likely to experience immune-mediated myositis. Elevidys should not be given to patients with deletion mutations involving exon 8 and/or exon 9 in the DMD gene, who are at the highest risk of this complication.
Anti-AAV antibodies
When the immune system encounters a virus, such as the AAV virus that’s used as a platform for Elevidys, it creates antibodies to help neutralize the threat.
Antivirus antibodies don’t distinguish between an infectious virus and the harmless vector used in gene therapies. Thus, when a person with high levels of anti-AAV antibodies is given an AAV-mediated gene therapy, their antibodies will stick to the therapy and neutralize it, which stops such treatments from working. Elevidys is not recommended for patients who have high levels of anti-AAV antibodies.
When patients who don’t have anti-AAV antibodies are administered an AAV-based gene therapy like Elevidys, their immune system will respond by making new anti-AAV antibodies in response to the virus. As a consequence, these virus-based gene therapies can only be administered once — and if a patient is given one AAV-based gene therapy, that individual usually is then ineligible to receive other AAV-based therapies in the future.
Ongoing studies are exploring strategies to reduce anti-AAV levels, which could potentially allow redosing of these therapies and make more patients eligible for treatment.
When will gene therapy be available for DMD?
Sarepta, the company that developed Elevidys, has not yet announced when the gene therapy will become available. Sarepta offers a patient support program, called SareptAssist, that provides information about insurance benefits, financial assistance, and other resources. The program can be reached by phone at 1-888-727-3782.
The Muscular Dystrophy Association has launched a Gene Therapy Support Network offering one-on-one information and support related to gene therapies for people diagnosed with DMD and other neuromuscular diseases.
Muscular Dystrophy News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about gene therapy for Duchenne muscular dystrophy
Elevidys, a gene therapy developed by Sarepta Therapeutics, was approved in the U.S. in June 2023 as a treatment for Duchenne muscular dystrophy (DMD). The therapy is designed to deliver to muscle cells a gene encoding micro-dystrophin, a shortened but functional version of the dystrophin protein that is missing in DMD. The U.S. Food and Drug Administration (FDA) granted accelerated approval to Elevidys based on early biomarker data suggesting it delivers micro-dystrophin to muscles as expected; clinical trials evaluating how the gene therapy affects disease progression are still ongoing.
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene that provide instructions for making the muscle protein dystrophin. The overarching aim of gene therapy for DMD is to deliver a functional version of this gene to muscle cells, allowing patients’ muscles to make a working form of dystrophin protein.
The gene therapy Elevidys was approved to treat some children with Duchenne muscular dystrophy (DMD) in the U.S. in June 2023. The therapy’s developer, Sarepta Therapeutics, priced it at $3.2 million per patient; although, according to the company, Medicaid and other programs might provide a discount, lowering the net price of Elevidys.
The U.S. Food and Drug Administration granted accelerated approval to the gene therapy Elevidys for Duchenne muscular dystrophy (DMD) based on biomarker data suggesting the treatment works as designed. Early data have suggested that children treated with the therapy tend to retain better motor function than is typically seen without treatment, but clinical trials to confirm whether and how this and other gene therapies might affect the progression of DMD are still ongoing.
Elevidys, the only gene therapy approved to date for Duchenne muscular dystrophy (DMD), can cause side effects including nausea, vomiting, fever, and low platelet counts. More serious complications, including liver damage, heart inflammation, and muscle inflammation, have been reported for Duchenne patients given gene therapy.
