Gene therapy for Duchenne muscular dystrophy
Fact-checked by Gene therapy is a treatment strategy for Duchenne muscular dystrophy (DMD) designed to target the underlying cause of the genetic disorder. Although this strategy can slow disease progression and help people with DMD retain better motor function for longer, it is not a cure.
Elevidys (delandistrogene moxeparvovec) is the only gene therapy currently approved in the U.S. for DMD. Several other experimental gene therapies are at various stages of development.
How gene therapies work in DMD
Broadly, gene therapy involves modifying genes in the body or introducing new genetic material to treat a disease. DMD gene therapy leverages these approaches to boost muscle health and slow disease progression.
The most common gene therapy approach tested for DMD involves supplying the body with a functional version of the DMD gene, which provides cells with instructions to make dystrophin, a protein that protects muscles from damage. Mutations in DMD cause Duchenne by reducing production of working dystrophin, leading to progressive muscle weakness and other symptoms.
Therapeutic genes are usually packaged into a carrier molecule to deliver them into a person’s cells. Modified adeno-associated viruses (AAVs) are commonly used for this because they aren’t known to cause disease in humans and are highly effective at entering human cells. Once the AAV introduces the therapeutic DMD gene into muscle cells, those cells will then use the genetic template to continuously produce more working dystrophin over the long term.
However, AAVs have limited carrying capacity and can’t hold a full copy of DMD, one of the largest genes in the human genome. As such, many gene therapies tested in DMD contain a shortened version of the gene that allows cells to make microdystrophin, a smaller dystrophin protein that can still help protect muscles.
Other investigational gene therapies for DMD don’t provide a new copy of the DMD gene, but instead work in other ways to boost muscle health. These include:
- gene therapies that deliver other muscle-protecting genes
- gene-editing technologies that alter the DMD gene that already exists in a patient’s cells to make it more functional
Approved and experimental DMD gene therapies
Sarepta Therapeutics’ Elevidys is the only gene therapy approved by the U.S. Food and Drug Administration for DMD, and is indicated for patients ages 4 and older who can walk. It delivers a DMD gene encoding microdysophin, packaged into an AAV-based carrier. Elevidys for DMD is given as a one-time infusion into the bloodstream. The FDA approved Elevidys in 2023; it is also approved in several other countries.
Several other investigational gene therapies for DMD are at various stages of clinical development. Many of these use a mechanism similar to Elevidys — they deliver a microdystrophin-encoding DMD gene — while others are testing new approaches. Some of the gene therapies in development for DMD include:
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| Therapy | Mechanism | Development Phase | Developer |
|---|---|---|---|
| RGX-202 | Delivers microdystrophin-encoding DMD gene | Phase 3 | Regenxbio |
| SGT-003 | Delivers microdystrophin-encoding DMD gene | Phase 3 | Solid Biosciences |
| GNT0004 | Delivers microdystrophin-encoding DMD gene | Phase 3 | Genethon |
| PBGENE-DMD | Edits a person’s own DMD gene | Phase 1/2 | Precision BioSciences |
| BBM-D101 | Delivers microdystrophin-encoding DMD gene | Phase 1/2 | Belief Biomed |
|
SRD-003 |
Boosts production of SERCA2a, a protein that protects the heart muscle, for people with DMD-related heart disease | Phase 1/2 | Sardocor |
Potential benefits and efficacy
Gene therapies are designed to slow or stop DMD progression, allowing patients to maintain better motor function for longer. Early clinical data for several therapies indicate that they lead to microdystrophin production, but the long-term effects of this on muscle health and motor function are still emerging from ongoing studies.
Clinical trials of Elevidys that supported its U.S. approval showed the therapy increased microdystrophin production, with some evidence that it may slow motor function declines. Ongoing trials are assessing the long-term effects of Elevidys on motor function.
Based on current understanding of gene therapies, there is no evidence that they help people entirely regain lost motor abilities or reverse disease progression — they are not considered a cure. Because of this, earlier treatment is generally recommended — people who receive gene therapy before the disease progresses very far may have the opportunity to maintain a higher level of muscle function, although this depends on the specific treatment.
Potential risks and side effects
Because gene therapies are introducing foreign materials into the body, the immune system can react against them. There are two types of types of serious immune reactions that have been linked to Elevidys, and potentially, with some other experimental therapies. These include:
- Immune-mediated myositis: Muscle inflammation believed to occur when the immune system attacks microdystrophin in muscle cells. Symptoms can include unexplained increases in muscle pain, tenderness, or weakness.
- Anti-AAV antibodies: The immune system produces antibodies against a gene therapy’s viral carrier, which can be preexisting or develop after treatment. This can compromise the treatment’s efficacy or safety.
The risk factors for immune-mediated myositis are not completely understood, but people with certain mutations may be at a higher risk. According to the Elevidys prescribing label, it shouldn’t be used by people with deletion mutations involving exon 8 and/or exon 9 of the DMD gene.
The potential development of anti-AAV antibodies after treatment is part of why most gene therapies are designed for one-time dosing, and preexisting antibodies may be a reason why a person can’t receive a gene therapy. Researchers are currently exploring strategies to prevent these antibodies from developing or degrade them in people who already have them.
Some gene therapies, including Elevidys, may also increase the risk of liver damage due to AAV accumulation in the organ, so regular liver monitoring may be needed.
Common Elevidys side effects include nausea and vomiting, fever, increased biomarkers of heart damage, and low levels of platelets, which help form blood clots. The side effects of other experimental therapies are still being investigated.
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