HNF is currently funding two important research projects: one targeting CMT type 1 and the other targeting CMT type 2A.

Charcot-Marie-Tooth, Type 1

CMT type 1 is caused by a defect in the gene responsible for producing PMP22, a critical component of the myelin sheath. The myelin sheath is the protective covering around axons (the nerve fibers that carry signals throughout the body). When PMP22 is affected, the myelin sheath is damaged, and without this insulation, nerve signals are weakened and often cannot reach target muscles. CMT type 1A involves overproduction of PMP22, while CMT type 1E involves a mutant form of PMP22. In either case, problems with the PMP22 protein cause demyelination (breakdown of the myelin sheath).

Researchers are pursuing several approaches to address this problem. Some hope to reduce or stop the overproduction of PMP22. Others aim to intervene after myelin damage has occurred, looking for ways to repair myelination or activate a neurorepair process within nerve cells.

HNF has chosen to fund research at the University of Southern California led by principal investigator Pragna Patel, PhD, who contributed to major discoveries in mapping the genetic causes of CMT. Dr. Patel’s research focuses on reducing the accumulation of PMP22 in nerve cells, whether the accumulation results from overproduction or from a mutant form of the protein.

The first step is developing a way to track the effects of drug compounds on the specific cell functions involved. Dr. Patel is creating a cell assay that links mutant PMP22 to a molecular marker capable of tracking the protein within the cell. A pilot version of this assay has produced strong results, showing clear differences in PMP22 accumulation when tested with two compounds: one known to reduce PMP22 and one known to increase it.

With this assay, Dr. Patel will be able to screen a library of tens of thousands of compounds for therapeutic potential in CMT, looking for those that either clear the overabundance of PMP22 within the cell or move PMP22 to the cell membrane where it belongs.

Charcot-Marie-Tooth, Type 2A

CMT type 2A is caused by a mutation in the mitofusin 2 gene, which is responsible for proper mitochondrial function. Mitochondria are the energy-producing structures in all cells, and this mutation impairs their function specifically in peripheral nerve cells. The result is insufficient energy within neurons, causing axons to degenerate over time. Developing treatments for CMT type 2A has been particularly difficult because a viable animal model that closely mimics the human disease has not been established. Mice produced with CMT type 2A have not consistently shown a progressive form of the disease.

HNF has chosen to fund research aimed at creating a reliable animal model, which is a prerequisite for testing any drug for CMT type 2A. This project is led by Dr. David Pleasure at the University of California, Davis. The research has made significant progress: mice with CMT type 2A recently gave birth to a litter of pups, and those pups are scheduled for thorough testing to determine whether their symptoms are close enough to the human disease to make them viable candidates for therapeutic research.