Research Progress in Charcot-Marie-Tooth Disease

Charcot Marie Tooth disease (CMT) is a group of genetic conditions affecting the peripheral nerves, which connect the brain and spinal cord to the rest of the body. It is commonly referred to as hereditary motor and sensory neuropathy (HMSN), and causes the motor and sensory nerves to become damaged and eventually die. This leads to weakness and wasting of the muscles below the knees and often those of the hands. It can also cause numbness or loss of feeling in the hands and feet (the ‘sensory’ component).

Visit our CMT resource page for more information on the condition and the support MDUK offers.


Over the last two decades, researchers have identified more than 80 genes in which mutations are known to cause CMT. These mutations usually affect the production of a particular protein in the peripheral nerves, either causing the protein to be faulty or not produced at all. How this then leads to damage of the peripheral nerves is not well understood for all types of CMT, however, many researchers around the world are looking into this.

The most common form of CMT is CMT 1A, which is usually caused by the duplication of a gene on chromosome 17. This gene carries the instructions for a protein called peripheral myelin protein 22 (PMP-22). Ongoing research is looking into the function of PMP-22, which is mainly found in Schwann cells. These cells provide support and protection for nerve cells and ensure that the insulating myelin sheath around the axon is properly functioning. This research has led to the conclusion that CMT 1A is majorly caused by the myelin sheath not working properly.

This research has led to the development of potential drugs that address the protection and maintenance of the myelin sheath and some of these drugs have been and are being tested in clinical trials (see below).

There is also ongoing research into different models of CMT, which help to improve understanding of the condition, as well as being a tool for testing potential treatments. There are several animal models, including mice and zebrafish, that have been established. Some researchers are also developing induced pluripotent stem cells (iPSCs) as models for some types of CMT. This type of stem cell is made from adult skin cells that are reprogrammed to become stem cells again. Researchers are looking into ways to differentiate iPSCs into Schwann cells, which are the cells mostly affected in people with CMT.


There is currently no specific treatment available that addresses the underlying genetic cause of CMT. However there are many scientists and companies conducting research in this area.

Gene therapy using adeno-associated viruses (AAVs) is being investigated as a potential treatment for CMT and many other muscle-wasting conditions (you can read more about AAV gene therapy in our feature article). Dr Kleopas Kleopa and colleagues in Cyprus have designed a gene therapy approach that could potentially treat CMT 1X. They have recently been awarded a two-year grant from the US Muscular Dystrophy Association and CMT Association to further this research (for more information, read this press release).

Professor David Bennett and his team in Oxford are developing a gene therapy that could potentially stop, slow down or even repair the damaged myelin in CMT. Their approach involves helping cells to produce a protein called neuregulin 1, or NRG1, which plays a role in controlling the production of myelin. This research is in relatively early stages and is being funded by Action Medical Research (find out more here).

The group of Dr Zarife Sahenk at Nationwide’s Center for Gene Therapy in the US are developing an AAV gene therapy that delivers the neurotrophin-3 gene (NT-3) to muscle. Neurotrophin is a growth factor that is responsible for the survival, development and function of nerve cells. In a mouse model of CMT, this gene therapy approach led to an improvement of motor function and transduction of the electrical signal (you can access their research paper here).

Some drugs have been developed to improve myelination and protect the nerve cells. For example, the company Pharnext have developed a combination of three drugs – PXT-3003 – that showed promise in animal models and is now in clinical trial for people with mild to moderate CMT 1A (see below). In 2014, PXT-3003 was granted Orphan Drug Designation from both the European Medicine Agency (EMA) and the Food and Drug Administration (FDA). Find out more on the Pharnext website.


In recent years we have invested a significant amount of funding into several research projects that are aimed at better understanding the underlying biology of the condition, testing new drugs and improving quality of life of people with CMT. Some of these were carried out in the group of Professor Mary Reilly at University College London (UCL).

Based on promising results in a mouse model, the first international clinical trial for CMT 1A was carried out. This aimed to determine if vitamin C could slow the progression of the condition. The results showed that while high doses of vitamin C were safe, unfortunately it did not improve the symptoms nor slow the progression of CMT 1A. The trial did however allow the scientists to gather important information on the progression of CMT 1A and to gain experience in conducting clinical trials for this condition. This will be valuable for future CMT 1A clinical trials.

Another project investigated whether exercise could lead to muscle damage in people with CMT. The researchers could find no evidence that exercise led to reduced muscle strength, but stated that they could not rule out that strenuous exercise could cause muscle damage. They concluded that individuals affected by CMT should be encouraged to exercise aerobically and that currently, rehabilitation continues to offer the best treatment.

We are currently co-funding Dr Andrew Shevchuk from Imperial College London who is investigating how mutations associated with some types of CMT affect an essential cell process called endocytosis. This allows cells to take up nutrients and replenish their cell membranes. Findings from this study will increase our understanding of the role of endocytosis in these conditions and could highlight potential therapeutic targets for the development of future therapies.

We are also funding Professor Henry Houlden at UCL who is investigating new genetic changes (or mutations) that lead to early-onset neuropathies. This will help give a better understanding of what is going wrong in these conditions and will help direct future research into potential treatments.


  • Increasing muscle mass by blocking myostatin

ACE-083 is an investigational protein therapeutic that binds and blocks the action of a family of proteins that negatively regulate muscle growth (including the myostatin protein). A phase 1 trial on healthy subjects showed that ACE-083 was safe and significantly increased the volume of the muscle that it was injected into. It has now been advanced to a phase 2 trial testing its safety and effectiveness in people with CMT1 or CMTX aged over 18. The trial is currently recruiting participants in the US only.

Clinicaltrials.gov identifier: NCT03124459

  • PXT3003

A phase 3 trial testing the safety and effectiveness of PXT3003 as a treatment for CMT1A is currently taking place in the UK and several other countries. This trial is an extension of a previous study and aims to demonstrate the effects of PXT3003 in the long-term. The inclusion criteria says you must have taken part in the previous study. PXT3003 is a novel combination of three repurposed drugs (baclofen, naltrexone and sorbitol). To read more about their mechanism of action, visit Pharnext’s website.

Clinicaltrials.gov identifier: NCT03023540

  • Mexiletine for muscle cramps

Mexiletine is a drug used to treat heart arrhthymias. This pilot study whether it could help to prevent muscle cramps in four adults with CMT. The trial was completed in December 2016 but results are yet to be released. We will keep you updated.

Clinicaltrials.gov identifier: NCT02561702

  • Ulipristal Acetate

Ulipristal Acetate is a drug that blocks the effect of the female hormone, progesterone. It is being tested in adult males with CMT1A as part of a phase 2 trial in France. This is based on pre-clinical data from CMT1A animal models showing that blocking progesterone reduced the synthesis of PMP22 and improved symptoms.

Clinicaltrials.gov identifier: NCT02600286


Updated August 2017

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