By: Keith Fargo, Ph.D., Chief Scientific Officer

Momentum is building in the development of gene therapies for Charcot-Marie-Tooth disease. Landmark back-to-back research publications offer innovative approaches to potentially curing the two most common forms of CMT.

What was published?

Two research studies were published in biomedical journals in March 2021, each describing innovative approaches to gene therapy in CMT.

1. Promising Results for CMT1A

A French research group from Inserm, a public scientific and technological institute in France, published results of a genetic treatment on two mouse models of CMT1A. A duplication of the PMP22 gene causes CMT1A. But instead of editing the gene’s DNA, the researchers took advantage of a naturally occurring process called RNA interference. This approach allowed them to target PMP22 messenger RNA for destruction, reducing the amount of PMP22 RNA — and therefore, PMP22 protein — produced by the gene duplication. In this experiment, the researchers activated the RNA interference process specifically in Schwann cells — the cells responsible for forming peripheral nerve myelin. The researchers injected the animals with genetic material called small interfering RNA (siRNA) to activate the RNA interference machinery.

As with many potential CMT therapies, getting the siRNA to the correct cells is a significant obstacle. When the researchers first treated the CMT1A model mice with plain siRNA, nothing happened. To overcome this hurdle, the researchers attached the siRNA molecules to nanoparticles formed from a naturally occurring lipid called squalene. These nanoparticles were able to carry the siRNA molecules to the peripheral nerves and deliver them to Schwann cells. The treatment caused a desired reduction in PMP22 RNA and protein levels. Promisingly, this resulted in regrowth and remyelination of axons, and the mice regained normal strength, balance, and nerve function.

Funding for this project was provided by the French National Research Agency (ANR).

2. Advancing Gene Therapy for CMT1X

The day after the above paper was published, an international research team with members in Cyprus, the United Kingdom and Sweden published their findings on using gene therapy to treat mice with CMT1X. CMT1X is caused primarily by mutations of the GJB1 gene that lead to the loss of functional connexin 32 protein (Cx32). To correct this, the researchers packaged a “normal” GJB1 gene into a viral vector (AAV9) capable of delivering its payload to cells in the body. Then, they considered how to ensure the genetic therapy works in Schwann cells, where the GJB1 mutations are thought to cause CMT1X. To do this, the researchers cleverly packaged another portion of genetic material called a “promoter” into the AAV9 vector along with the GJB1 gene. When a gene is under the control of a promoter, it will be expressed when (or where) the promoter is activated. Because the researchers in this study used the MPZ promoter, the “normal” GJB1 was turned into Cx32 protein specifically in Schwann cells.First, the researchers tried the treatment in young mice that had not yet developed symptoms. Over time, untreated mice developed disease symptoms, but those treated with the gene therapy did not. Next, the researchers tried treating older animals that had already developed disease symptoms. Remarkably, even after just a single treatment, the mice improved in every measure, including strength and nerve structure and function.

Principal funding for this project was provided jointly by the Charcot-Marie-Tooth Association (CMTA) and the Muscular Dystrophy Association (MDA).

When can patients expect to benefit from these treatments?

While these papers are very exciting to the research community, it is important to remember that these studies were performed in mice. Even the most promising studies in mice must be confirmed with additional research, usually including research in another animal model, before being considered for human clinical trials. Because of this, these potential therapies need further development before they are ready for use by CMT patients. However, these studies provide critical proof of concept that we can solve the delivery challenges associated with CMT. It is not a matter of if but of when.

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How is the CMT Research Foundation advancing gene therapies?

The CMT Research Foundation has prioritized the development of gene therapies and delivering gene therapies specifically to the cells of the peripheral nerves. In fact, more than half of the projects we have launched address these research areas directly. Here are some examples:

• Similar to the Inserm project, a CMT Research Foundation-funded project with DTx Pharma developed an RNA interference-based therapy for CMT1A. Based in part on the strength of these studies, DTx recently received $100 million in funding that will, in part, be used to continue the CMT1A project, looking toward clinical trials.
• Kleopa at Cyprus Institute of Neurology and Genetics, who worked on the published CMT1X project, is funded by the CMT Research Foundation to take a similar approach to CMT1A, with promising early results.
• The CMT Research Foundation is also funding Drs. Garcia and Lorson at the University of Missouri to study a “knockdown and replace” approach to genetic therapy in CMT2E, which is caused by mutations of the neurofilament light gene.

While these projects are focused on CMT1A and CMT2E, success will be translatable to many different forms of CMT.

Read more about all the research we fund.

Looking to the Future: Speeding Treatments Together

2021 continues to be a promising year for CMT research, but continued investments in research are critical to speed scientific discovery. Together, we must take advantage of this momentum. Your donation to the CMT Research Foundation is the most meaningful way to accelerate progress to deliver CMT treatments during our lifetime.