Leukodystrophies are a set of rare genetic disorders that affect how the central nervous system functions. Since these disorders are all caused by a faulty genes, gene therapy might be able to help.

Leukodistrophies are genetic disorders that lead to the deterioration or malformation of the myelin sheath, a fatty insulation that wraps around nerve axons and is essential 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, which can impair walking, speech, and vision.

Treatment Pipeline

Cerebral ALD: Lenti-D

Bluebird Bio, a biotechnology company, is currently developing a gene therapy for the treatment of cerebral adrenoleukodystrophy (CALD). The therapy, known as Lenti-D, is currently in a phase 2/3 clinical trial. A combination of phase 2 and phase 3 is designed to accelerate drug development. So far results have shown a substantial impediment in disease progression of patients.

Fabry Disease: AVR-RD-01

AVROBIO, a clinical stage gene therapy company, is working on a gene therapy approach to help patients with classic Fabry disease. The therapy is currently in the early phases of two different clinical studies.

MLD: OTL-200

Orchard Therapeutics, an integrated biopharmaceutical company, is helping to develop a gene therapy treatment for metachromatic leukodystrophy (MLD) called OTL-200 that has made it past phase one of clinical trial.

MLD: HMI-202

Homology Medicines, a genetic medicines company, has started pre-IND (Investigational New Drug) studies for an in-vivo gene therapy that will target the faulty ARSA gene found in the late infantile form of MLD. Once an IND application has been submitted and approved by the FDA, then the study can move to the first phase of human trials.

Preclinical Studies

There are a variety of preclinical studies underway for other Leukodystrophies, including Canavan Disease and Krabbe Disease. Preclinical studies need to happen before a clinical trial can begin. This stage uses cell culture and animals to find out if a treatment is safe and potentially successful.

Pathway to Treatment

Diagnosis: Sooner is Better

Leukodystrophy symptoms typically show up within the first two to five years of a patient’s life. If myelin sheath surrounding neurons are damaged can have neurodegeneration or decline that is irreversible. It is best to get a diagnosis as early as possible. In the case of CALD, early diagnosis can be made through screenings completed for newborns. Unfortunately, many states do not include leukodystrophy in their standard screenings. Diagnosis can also involve evaluating family health history and specialized testing. Genetic testing can detect mutations in the genes that can cause these disorders. Parents can consider genetic testing before or during pregnancy to determine if the child is at risk.

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Let's Compare

To better understand the effect leukodystrophy has on the body, let's compare the body to a factory. Starting with the specialized fatty molecules that are required for myelin to function, which are crafted step-by-step by cells called glia. Within these cells are enzymes that function almost like factory workers on an assembly line. When an enzyme isn’t able to perform the job—similar to an assembly worker who falls asleep—excessive buildup of “product” occurs, causing disease in the body. A malfunctioning factory causes an accumulation of unfinished products. Or in this case—the fatty molecules needed for myelin function.

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How Gene Therapy Can Help

There are over forty types of leukodystrophies that we know of. A few more common disorders being researched include Cerebral Adrenoleukodystrophy (CALD), and Metachromatic Leukodystrophy (MLD). The diseases are different, as they are all caused by a different faulty gene that produces a key protein. For example, ALD is caused by a faulty gene called ABCD1, which creates a protein called ALDP that helps break down fatty acids. If these fatty acids accumulate without ALDP, they damage the myelin sheath.

Gene therapy helps introduce a corrected version of the gene to the cell in charge of creating key proteins. This is done by using a vector—which is often a virus without the disease causing parts—to deliver the working gene into the cells. The corrected cells then produce the protein that was missing or defective prior to treatment, aiming to halt disease progression.

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The Role of Stem Cells

Stem cells may hold the key to some Leukodystrophy gene therapy treatments. Stem cells are undefined cells that give rise to specific cell types, depending on what the body needs. Currently hematopoietic stem cells (HSC) transplantation is the standard therapy for CALD. Functional HSCs can clar up the accumulated fatty acids and decrease inflammation. However, a transplant carries significant risks and problems with donor availability. An ex-vivo gene therapy uses the patient’s own stem cells, meaning they are removed from the patient and then altered.

In this treatment, HSC’s are removed via a blood draw, and then modified using a vector to deliver a working copy of the faulty gene. These modified genes with in the HSCs are then returned to the body. For this procedure, chemotherapy may be needed to clear out the bone marrow for the newly functional cells. However, since the gene therapy approach utilizes the patient’s own cells, there is no risk for immune system complications.

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You may be curious of how patients can participate in clinical trials as a way to receive an investigational treatment at no cost, while also benefiting the medical community and others who have the disease. If you think you or your child may be eligible for a clinical trial, it’s best to speak with your primary care physician first to learn more and determine if it is right for you. Then, 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.

For reference, here’s some examples of the (many) eligibility criteria for patients to participate in a clinical trial for a childhood Cerebral Adrenoleukodystrophy (CCALD) 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.

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At this time, we do not know if or when this gene therapy will be approved by the FDA and commercially available. The therapy candidate furthest along is currently at phase 2/3 of clinical investigation. The overall process may take several more years, until it is deemed safe and effective.

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Get Involved

One way you can help is to become involved with a patient advocacy organization. They work hard to fund research and advocate for newborn screenings. They are also a great way to connect with other families and patients affected by various leukodystrophies if you’re looking for support and advice. The diseases may be rare, but you're not alone.

ALD Connect

Hunter’s Hope


United Leukodystrophy Foundation

The Calliope Joy Foundation

The Myelin Project

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Developing A Treatment

How do clinical trials work? Gene therapies take years to go from theoretical concepts, to preclinical trials, to clinical trials, and, finally, into actual treatments that can improve the lives of patients. Here we learn about the process of developing a treatment.

Different Approaches

Gene therapy, cell therapy and gene editing are fields with a similar goal: To treat disease by changing our bodies at a microscopic level. What do these approaches have in common, and what makes them different?


X-linked myotubular myopathy, otherwise known as XLMTM, is a rare genetic disorder that primarily causes muscle weakness. The disease is severe and often leads to premature infantile death. Fortunately, there is opportunity for gene therapy to improve the lives of those with XLMTM.


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