X-linked myotubular myopathy, also known as XLMTM, is a genetic disorder that primarily causes muscle weakness. Learn how gene therapy may target the cause of disease to slow or stop its progression, along with helpful information on clinical trials, and staying informed.
About XLMTM
Cause of disease - XLMTM is a genetic disorder that causes muscle weakness. The protein, myotubularin, which helps us to breathe and swallow, is not being made in proper amounts. This is due to a gene variant (also known as a gene mutation) which is a change to a person’s genes that can lead to a disorder. Individuals with XLMTM may require a ventilator to support breathing and a feeding tube for nourishment.
Symptoms - XLMTM often show up at birth and can be described as “floppy” because the muscles appear weak. XLMTM can be confirmed once a change in the MTM1 gene is detected. This disease is mostly seen in males because it is a variation of a gene on the X chromosome (also known as “X-linked”). However, female carriers can also show symptoms of muscle weakness, usually in later adulthood. Speak with a provider about the option of genetic testing before or during pregnancy to determine if the child is at risk for MTM.
Gene Therapy Approach
The gene therapy approach aims to be a one- time treatment that delivers a working MTM1 gene into cells cells. The vector used to deliver the new working gene is called an adeno-associated virus (AAV). A viral vector is used as a carrier to deliver the working gene. Scientists know that viruses are good at getting into cells, so they have learned how to safely use this ability to deliver working genes. But don’t worry, the viral genes are removed, so only therapeutic (intended) genes are delivered. Think of a viral vector as an envelope with a message inside. The harmful letter that could cause disease is taken out of the envelope and replaced with a new gene that has a specific message for the cells. Once delivered, the working gene gives instructions to the cells to create more of the needed protein. The goal is to increase production of myotubularin protein causing the weakened muscles to contract more which should improve muscle performance and breathing. The goal is to prevent, slow, or stop disease progression.
Treatment Pipeline
Gene therapy approaches for XLMTM are being investigated in preclinical studies and clinical trials. 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 active and recruiting 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. For XLMTM, a key factor is age because if affects how a person’s body operates. For example, with an older patient, the disease may have had more time to do damage in the body. A younger patient may still be able to see results where the disease’s effects are slowed or stopped. Basically, an age limitation allows the researcher to better understand dosing and results of the therapy. Down the road, as the treatment moves through the phases of development and if it eventually gets approved, the next goal would be to expand the treatment to reach more individuals suffer by spanning various ages and classifications of the disease.
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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 this gene therapy will be approved by the FDA (or the EMA for therapies in Europe) and commercially available to individuals with XLMTM. 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
A number of organizations provide individuals with MTM disorders, and their families, with resources, research updates, and support: