Approved Research

Genetic architecture of the rare monogenic disease Charcot-Marie-Tooth Type 1A and of other Charcot-Marie-Tooth diseases

Lay summary

Charcot-Marie-Tooth diseases (CMTs) are inherited neuromuscular disorders that affect 1/2,500 individuals. Common symptoms include loss of muscle and sensation in legs and feet, decreased ability to run, abnormal gait, frequent falling. Most severe cases may be unable to live a normal life due to high difficulty carrying out fine motor skills of the hands, feet, fingers, tongue, and may suffer severe pain in leg muscles. For milder cases, those diseases are often misdiagnosed as clumsiness and lack of coordination. Most CMTs result from an anomaly of a single gene. For instance, CMT1A is caused by the mutation of a gene called PMP22, which alters the transmission of the electric signal to the nerves of the legs, arms, hands. It affects 1/10,000 individuals, and, as for all other CMTs, there is no approved treatment against it. Pharnext has developed a combination of three repurposed drugs, at low-dose so that to limit potential side effects, which slows down the progression of CMT1A (international randomized, double-blind Phase 3 clinical trial).

The treatment was developed based on the idea that the causal gene of the disease interacts with other genes in the cell and that, together, they form a network of molecular reactions that are imbalanced by the causal genetic mutation. We identified pre-existing drugs that could act on components of this molecular network and which, combined, could dampen the impact of the causal mutation on the nerves.

The goal of this research is to expand the number of genes that, in addition to the main causal mutation, have an impact on CMT1A and other CMTs. Each identified gene is an opportunity to research drugs that could target this gene and, ultimately, the disease. Since CMT1A and the other most common CMTs are clinically diagnosed by genetic analysis, performing extensive, genome-wide genetic analysis of the UKB cohort should allow us to identify additional CMT individuals and better characterize mutations associated with the disease. In addition, some individuals who are not affected by CMT may be affected in their neuromuscular traits by other genetic mutations. Identifying such mutation and their genes using the UKB will allow us to dissect the molecular basis of neuromuscular traits, which are also affected by the CMTs. Ultimately, this research will help develop and tailor future treatments and help define the molecular determinants of neuromuscular disorders.