Muscular dystrophy is a group of genetic diseases that cause progressive muscle weakness and loss of muscle mass. There are a wide variety of muscular dystrophies, each caused by different gene mutations. For certain diseases, including limb-girdle muscular dystrophy (LGMD) and Duchenne muscular dystrophy (DMD), gene therapy might offer hope for slowing and managing symptoms.
ELEVIDYS is an FDA-approved gene therapy for the treatment of children aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed gene variation or mutation in the DMD gene.
Gene Therapy Approach for DMD
The most common form of muscular dystrophy is called Duchenne. The disease is caused by a faulty gene that interferes with how muscle cells produce a protein called dystrophin. It’s part of a vital protein complex that works to strengthen and protect muscle fibers. Our muscles need dystrophin to function properly, otherwise they become weak and muscle mass is lost. Symptoms of Duchenne can start as early as toddler years, affecting muscles that move the hips, thighs and shoulders. The disease also affects the heart and respiratory muscles, leading to life-threatening complications.
There is no known cure for DMD. However, gene therapy may be able to slow the progression of the disease. Gene therapy introduces into cells a working version of a gene that is in charge of creating key proteins and enzymes, such as dystrophin. These genetic instructions are delivered to the cells using a vector. Vectors are often derived from viruses because they are capable of entering cells to deliver genetic material, such as a working gene. But don’t worry, all viral genes are removed and the vector is modified to only deliver therapeutic genes into cells.
Our genes come in a wide range of sizes, and the gene that instructs cells to create dystrophin is one of the largest known genes in our genome. The gene’s size prevents it from being delivered within the preferred vectors for gene therapy. Therefore, a smaller version of the gene called micro or mini-dystrophin has been developed by researchers to fit inside small vectors like those based on adeno-associated viruses (AAVs).
Current Treatments
FDA-approved gene therapy ELEVIDYS is an adeno-associated virus based gene therapy for the treatment of children aged 4 through 5 years with Duchenne muscular dystrophy (DMD) who have a confirmed mutation in the DMD gene.
It is important to inform your primary medical provider or hematologist to find out if a gene therapy is the best option for you and to understand health insurance coverage as well as short- and long-term risks. Gene therapy can be an alteration for the lifetime so people should be aware that there may be long-term effects (both good and bad) that are not known at this time.
Gene Therapy Approach to Limb-Girdle Muscular Dystrophy
One muscular dystrophy sub-group is called limb-girdle muscular dystrophy, or LGMD. These diseases weaken the muscles of a person’s shoulders, upper arms, hips and thighs. Each subtype of LGMD is caused by a different inherited faulty gene. Some are due to dominant gene mutations and are classified as LGMD D (previously LGMD type 1), while others caused by recessive gene mutations are known as LGMD R (previously LGMD type 2). These dominant and recessive genetic distinctions play a key role in how gene therapy treatments are developed.
Although it is not a cure, gene therapy may be able to slow the progression of LGMD. Gene therapy introduces a working version of a gene into a cell in charge of creating key proteins or enzymes. These genetic instructions are delivered to the cells using a vector. Vectors are often derived from viruses because they are capable of entering cells to deliver genetic material, such as a working gene. But don’t worry, all viral genes are removed and the vector is modified to only deliver therapeutic genes into cells.
Due to the variety of LGMDs, each gene therapy treatment would need to be designed to specifically target each mutated gene of each subtype. For example, LGMDs caused by a recessive gene mutation would mean that no functional protein is actually being produced in the first place. Gene therapy would need to deliver a working gene into muscle cells to help them produce the missing protein. But in the case of a LGMD caused by a dominant gene mutation, gene therapy would need to actually deliver a gene that could block the dominant mutated gene from creating the abnormal protein. This blocking approach is called antisense therapy.
Pathway to Treatment
Treatment Pipeline
Gene therapy for different types of MD are being investigated in clinic trials and preclinical studies. Clinical trials are a required part of the research process that help scientists understand the way a drug or treatment will interact with the human body and whether it is safe and effective. Preclinical studies are an even earlier stage of research that test the safety and effectiveness of a treatment in animal or cell-based models before proceeding with a human clinical trial. Clinical trials may differ on various aspects of their design. Speak with a trusted provider or member of the clinical trial research team if you are considering participating in a clinical trial.
To stay up to date on open clinical trials in the U.S. or globally, visit the ASGCT Clinical Trials Finder and search using the "diagnosis" filter.
Participating in a Clinical Trial
It is important to be well informed when deciding to participate in a clinical trial. Below are some key points to consider. Visit the considering a clinical trial page for more information and resources to help guide you.
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Eligibility - Eligibility for a trial is based on strict inclusion and exclusion criteria. These are specific factors that determine whether a person can or cannot enroll in a clinical trial. This is an important way for researchers to understand if the gene therapy is working properly and to ensure participant safety. Other criteria may include factors such as how advanced the disease is, or previous use of treatments. Speak with a healthcare provider or a member of the clinical trial research team to help determine if you may be eligible for a clinical trial.
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Risks - As with any medical intervention, there are risks that need to be carefully considered. Before participating in a clinical trial, a member of the research team should review any potential risks and benefits with the patient or caregiver. Therapies being studied in clinical trials are not a guaranteed cure and cannot guarantee beneficial results. There is always a chance that the investigational treatment may not work. In the event a person is not satisfied with the outcome, the person may not receive another dose of the gene therapy. In addition, participating in a clinical trial may prevent future participation in other trials or from receiving other types of treatments. Gene therapy can be an alteration for the lifetime, so people should be aware that there could be long term effects (both good or bad) that are not known at this time.
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Benefits - Participating in a trial may offer many potential benefits compared to not receiving any form of intervention for a fatal disease. Gene therapy aims to be a one-time treatment with lasting positive effects that slow or stop disease progression for a lifetime. However, there is no guarantee. If gene therapy is received earlier in the course of disease, it has the potential to stop damage before it occurs.
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Long-term follow up - It is the patient’s responsibility to comply with the long-term follow-up of a trial. The Food and Drug Administration (FDA) guidelines require the clinical trial research team to monitor safety and potential long-term effects of a gene therapy. Follow up may require in-person appointments that vary in frequency and location, or completion of mailed packets with response forms. The need for long-term data collection for a gene therapy trial can last up to 15 years—another reason to consider all outcomes and responsibilities that come with committing to a clinical trial. There are a limited number of participants in trials so a lack of attendance at follow-up appointments leads to not enough study data. This could negatively affect FDA approval of a new therapy and thereby limit access to the therapy by patients who did not participate in the clinical trial.
Access
At this time, we do not know if or when more gene therapies will be approved by the FDA and commercially available for people living with muscular dystrophies. . The overall process may take several more years, until it is deemed safe and effective by the FDA or regulatory agencies in other countries.
Stay Informed
One way you can help is to become involved with a patient advocacy organization. They are a great way to connect with other families and patients affected by muscular dystrophies if you’re looking for support and advice. The diseases may be rare, but you're not alone.