Cerebral adrenoleukodystrophy (CALD), and metachromatic leukodystrophy (MLD) are rare genetic conditions that affect how the central nervous system functions. Both disorders are caused by a different faulty gene that leads to the myelin sheath being weak or misshapen. The myelin sheath is a fatty lining that wraps around nerve axons and is vital for proper neuron function. When the myelin sheath is altered it makes it hard for our nervous system to send messages to different parts of our body. This can impair walking, speech, and vision. Learn how gene therapy could slow or stop the progression of this disease, along with helpful information on clinical trials, and resources to stay informed on the research landscape.
SKYSONA is an FDA-approved gene therapy for boys aged 4 – 17 years old with early, active cerebral adrenoleukodystrophy (CALD).
LENMELDY is an FDA-approved gene therapy for infants and children with metachromatic leukodystrophy (MLD) who gave not yet exhibited symptoms and children with early stage MLD.
About CALD
There are over forty types of leukodystrophies that we know of. Two leukodystrophies being researched for gene therapy are CALD and MLD, which are each caused by a different faulty gene that produces a key protein. ALD is caused by a faulty gene called ABCD1, which creates a protein called ALDP that helps break down fatty acids. Without working ALDP, these fatty acids accumulate, which damages the myelin sheath. Roughly 40 percent of boys with ALD will develop the most severe form of the disease—CALD. This can also occur in adult males. If left untreated it— leads to rapid brain and nerve decline.
About MLD
There are three types of MLD based on the age symptoms appear—late infantile, juvenile, and adult. MLD is often caused by a faulty gene called arylsulfatase A (ARSA). This gene produces a protein that helps to clean up the cell. This “clean-up duty” includes breaking down sulfatides, which are fats present in the myelin sheath. Without proper cleanup, the accumulation of sulfatides damages the myelin leading to progressive decline of brain and motor function.
Gene Therapy Approach
Gene therapy introduces a working version of the faulty gene into the cells in charge of creating key proteins. This is done by using a vector—which is often derived from a virus, but the viral genes have been removed. Only therapeutic genes are delivered into the cells. The modified cells then produce the protein that was missing or defective prior to treatment.
Stem cells are undefined cells that give rise to specific cell types, depending on what the body needs. With gene therapy, hematopoietic (blood) stem cells (HSCs) are removed via a blood draw. Then the cells are modified using a vector to deliver a working copy of the faulty gene. This is ex vivo gene therapy, meaning the cells are removed from the patient and then altered. These modified HSCs containing the working copy of the gene are then returned to the body. This treatment aims to be one-time and to halt disease progression.
For this procedure, chemotherapy may be needed to clear out the bone marrow to make room for the modified HSCs. However, the gene therapy approach utilizes the patient’s own cells (autologous), which minimizes the risk of immune system complications that may occur with donor transplants. Currently, HSC transplantation using donor (allogeneic) stem cells is the standard therapy for cerebral ALD and MLD. However, a donor transplant carries significant risks and is limited by donor availability.
FDA-Approved Therapies
SKYSONA is an FDA-approved gene therapy for boys aged 4 – 17 years old with early, active cerebral adrenoleukodystrophy (CALD).
LENMELDY is an FDA approved one-time cell-based gene therapy utilizing a lentiviral vector for the treatment of individuals:
It is important to inform your primary medical provider or neurologist to understand if a gene therapy is the best option for your child.
Treatment Pipeline
Further gene and cell therapy approaches are being researched in trials for different types of the disease such as CALD, MLD, Canavan disease, and Krabbe disease. 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. 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.
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. These criteria may include factors such as age, physical ability, medical history, and more. For CALD, individuals can be excluded if they have any clinically significant cardiovascular or pulmonary (heart or lung) diseases or conditions. 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 may not be able to 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 and 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.
Genetic Testing and Diagnosis
Leukodystrophy symptoms typically show up within early childhood. If the myelin sheath surrounding neurons is damaged, it can result in neurodegeneration (decline) that is irreversible. It is best to get a diagnosis as early as possible. Diagnosis can also involve checking family health history and obtaining specialized testing, such as genetic testing. Genetic testing can detect mutations or variations in the genes that can cause these disorders. Parents can consider requesting genetic testing before or during pregnancy to determine if the child is at risk.
Early diagnosis for ALD can be made through screenings completed for newborns. Although an increasing number of U.S. states have recently been adding ALD to their standard newborn screening panels, there are still many which do not. Visit the websites for EveryLife Foundation or the patient organizations listed below to advocate:
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 leukodystrophy. The overall process may take several more years, until it is deemed safe and effective by the FDA.
Stay Informed
A number of organizations provide individuals with different types of leukodystrophy and their families, with resources, research updates, and support: