By: Keith Fargo, PhD, Chief Science Officer

The CMT Research Foundation is pleased to announce a new project with Samsara Therapeutics, a US/UK-based biotech company that is developing a novel class of drugs for CMT1A.

CMT1A is caused by duplication of a stretch of DNA that includes the PMP22 gene, and people with CMT1A produce approximately 33% more PMP22 protein than people who do not have CMT1A. While the mechanism of disease is not known precisely, this overproduction of PMP22 impedes the normal inclusion of PMP22 in the myelin sheath produced by Schwann cells in the peripheral nerves, leading eventually to demyelination, axon loss, and disability. One hypothesis about how PMP22 gene duplication causes CMT1A is that the extra PMP22 protein clumps together to form aggregates that are toxic to the peripheral nerves. And in fact, PMP22 aggregates have been found in the nerve cells of CMT1A model mice who are genetically engineered to overproduce PMP22. Other neurodegenerative diseases in which toxic aggregates are thought to play a role include Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.

Fortunately, the body has a cellular process – called autophagy – for breaking down and recycling damaged or dysfunctional proteins. The CMT scientific literature suggests that in CMT1A, the body initially responds to PMP22 over-expression and aggregation by boosting autophagy. However, over time, the body is unable to keep up with the continual over-production of PMP22 and the autophagy system is overwhelmed. Therefore, increasing the capacity of the body’s autophagy system may slow, prevent, or even reverse nerve damage caused by PMP22 over-expression.

Samsara Therapeutics has discovered a number of drug-like molecules called autophagy enhancers that stimulate the body’s natural autophagy process. In an early preclinical study, they showed that this class of drugs improves outcomes in CMT1A model mice, reducing PMP22 protein levels and restoring measures of nerve structure and function.

This partnership will allow Samsara to further develop these molecules and prepare for potential clinical trials. The project is divided into two broad sets of activities – compound optimization and IND-enabling studies. In the compound optimization stage, the researchers will produce chemical derivatives that have even better drug properties than the current compounds. Activities in this stage will focus on effectiveness and safety measures and are expected to result in the selection of one compound to move forward as a ‘lead candidate.’ In the IND-enabling studies stage, the researchers will carry out a series of experiments with the lead candidate to prepare for clinical trials. In the United States, companies must submit an Investigational New Drug (IND) application to the FDA and receive permission to begin human clinical trials. ‘IND-enabling studies’ refers to a prescribed set of experiments that must be completed in Petri dishes and model animals to form the basis of the IND application to the FDA. If the project is successful, therefore, it will result in the identification of a lead candidate and a data package to submit to the FDA ahead of potential clinical trials