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.
DMD and Gene Therapy
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).
Limb-Girdle Muscular Dystrophy and Gene Therapy
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
Investigational gene therapies for LGMD and DMD are being researched by Sarepta, Genethon, Solid Biosciences, Editas, Pfizer, Asklepios, and Axovant. Treatment is currently in development for the LGMD subtypes 2E (β-sarcoglycan), 2D (α-sarcoglycan), 2B (dysferlin), 2I (FKRP), 2A (calpain, and 2L (anoctamin 5). To learn more about any active and recruiting gene therapy clinical trials, visit the ASGCT Clinical Trials Finder and search for limb-girdle or Duchenne muscular dystrophy in the “diagnosis” field.
Gene Editing and DMD
Researchers are also exploring approaches for DMD using gene editing, which is a type of gene therapy, to increase dystrophin production. Gene editing seeks the same outcome as other types of gene therapy—to influence how cells produce key proteins or enzymes. However, the goal of gene editing is to remove, disrupt or correct faulty elements of DNA within the gene rather than replace or add a gene. Gene editing uses systems that are highly precise to make this change inside the cell. The cells can be from the patient or donor. There are no approved gene editing treatments yet, but many are currently being researched in clinical trials.
Eligibility
You may be curious how people with LGMD and DMD can participate in clinical trials for gene therapy. These trials offer an opportunity to receive an investigational treatment at no cost, while also benefiting the medical community and others who have the disease. Eligibility, risks and benefits should be discussed with the individual’s disease specialist or primary care provider.
To participate in a clinical trial, the individual must meet strict eligibility criteria, such as age, gender and treatment history. A key barrier can be the time of diagnosis. If a person is administered a treatment earlier in life, the disease hasn’t had years and years to affect the body yet and the treatment can be more effective.
Get Involved
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.