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CALD and MLD

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Cerebral adrenoleukodystrophy (CALD), and metachromatic leukodystrophy (MLD) are rare genetic disorders 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 can target the cause of these disorders, along with helpful information on diagnosis, clinical trials, and staying informed.

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.  

Treatment Pipeline

There are gene therapy approaches for different types of the disease such as CALD, MLD,  Canavan disease, and Krabbe disease. Preclinical studies and clinical trial research and development of these therapies is being done by companies including bluebird bio, Orchard Therapeutics, and Homology Medicines.  

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.

Pathway to Treatment

Diagnosis: Sooner is Better

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 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:

  • For your state to include ALD in its newborn screening panel.
  • For MLD to be added to the Recommended Uniform Screening Panel (RUSP). This is a list of disorders that the Secretary of the Department of Health and Human Services (HHS) recommends for states to screen as part of their newborn screening panel.

Eligibility

Speak with your primary care physician to help determine if you or your child may be eligible for a clinical trial. The individual must meet the eligibility criteria, which can be based on the age at the time of dosing, physical ability, past medical treatment, and more. Go to Considering a Clinical Trial to learn more about informed consent, physical preparation, lifestyle preparation, and long-term follow up.

For reference, here are some examples of the many eligibility criteria for patients to participate in a clinical trial for a childhood cerebral adrenoleukodystrophy (CALD) gene therapy treatment. Patients can be eligible if they are male and aged 17 years or younger at the time of guardian consent to participate. Patients can be excluded if they have any clinically significant cardiovascular or pulmonary (heart or lung) diseases or conditions.  

Access

At this time, we do not know if or when gene therapies will be approved by the FDA and commercially available for the different types of leukodystrophy. The therapy candidate furthest along is currently at phase III of clinical investigation. The overall process may take several more years, until it is deemed safe and effective.

Stay Informed

There are many patient advocacy organizations to follow or get involved with. They work hard to fund research and advocate for newborn screening policies. They are also a great way to connect with other families and patients affected by various leukodystrophies if you are looking for support and advice. 

Last Updated: 02/18/2021

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