GM1 gangliosidosis (GM1) is a rare genetic disorder that progressively damages cells primarily in the brain and spinal cord, and other tissues as well. 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.
ASGCT will release resources on GM2 (Tay-Sachs and Sandhoff disease) in the coming weeks.
About GM1
Cause of disease - GM1 is classified by age of disease onset. This includes infantile (Type 1), late infantile or juvenile (Type 2), and adult/chronic (Type 3). All forms of GM1 are caused by mutations (e.g. changes) to the GLB1 gene. This gene instructs cells to produce an enzyme called beta-galactosidase (ß-gal), which breaks down fats and sugars in the lysosomes within cells. Often referred to as the “recycling center” of cells, lysosomes break down and remove waste to allow cells to function properly. As a result of the faulty GLB1 gene, waste accumulates in cells and tissues. Build up of waste can eventually be toxic to cells and tissues in the body and result in dysfunction or even cell death.
Symptoms – GM1 Type 1 is the most severe form of the disease. People with Type 1 typically present with symptoms around six months of age when development may begin to slow and muscles may become stiff or weak, with an eventual loss of motor skills. Common characteristics for this form are a cherry-red spot on the eye, difference in facial appearance, and enlarged gums. People with GM1 Type 2 typically have a period of normal development that is followed by a decline in motor skills beginning between 18 months and 5 years old (e.g. toddler or school-age). GM1 Type 3 is a milder form of the disease and age of symptom onset varies. GM1 Type 3 is sometimes misdiagnosed as Parkinson’s disease.
Gene Therapy Approach
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Gene therapy is being researched to potentially treat infantile, late infantile, and juvenile-onset types of GM1. Gene therapy for GM1 aims to be a one-time treatment that delivers a working copy of the GLB1 gene into cells using a viral vector. The GLB1 gene instructs cells to make the ß-gal enzyme. Scientists know that viruses are good at getting into cells, so they have learned how to safely use this ability as a carrier to deliver working genes. But don’t worry, the viral genes are removed, so only therapeutic (intended) genes are delivered. The goal is to restore how lysosomes function which is to remove and prevent the build up of toxic materials.
Gene therapy for GM1 may be given through different routes. One way is through an injection at the base of the skull, known as an intracisternal or intra-cisterna magna injection. The gene therapy is administered into a space containing fluid that surrounds the brain and spinal cord. Another approach is to inject the gene therapy into a vein, known as an intravenous injection. Then, the gene therapy travels throughout the body in the bloodstream. Clinical trials may differ on various aspects of their design, including on the route of gene therapy administration. If you are considering a clinical trial, it would be best to discuss your options with a healthcare provider or a member of the clinical trial research team.
Treatment Pipeline
There are active gene therapy clinical trials for GM1, and ongoing preclinical studies. Clinical trials are a required part of the research process that aims to 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 to confirm the safety and effectiveness of a treatment in animal or cell-based models before proceeding with a human 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
There is currently no effective medical treatment for GM1, only treatments for some of the signs and symptoms, but those do not alter disease progression. Therefore, some may consider an investigational gene therapy as an option. It is important to be well informed when deciding to participate in a clinical trial. Below are some key points to consider. Go to 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. These criteria may include factors such as age, how advance the disease is, medical history, and more. Speak with a healthcare provider or a member of the clinical trial research team to help determine if you or your child 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 cannot 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 any 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 gene therapies will be approved by the FDA and commercially available for people living with different types of GM1. The overall process may take several more years, until it is deemed safe and effective by the FDA.
Stay Informed
There are many patient advocacy organizations to follow or get involved with. They work hard to fund research and advocate for patient and family needs. They are also a great way to connect with others affected by the disease if you are looking for support and advice.
Was this information helpful? If so, please feel free to share these resources by referencing the GM1 media kit!