CMT is unlike other neuromuscular disorders because its causes have been pinpointed, leading to the identification of at least 33 specific gene defects. More importantly, the fact that these genetic mutations can be replicated in laboratory models and grown as tissue cultures opens an extraordinary window of opportunity to develop treatments and cures for CMT in the immediate and foreseeable future.

To accomplish these goals, the Charcot-Marie-Tooth Association (CMTA) has partnered with Nike to established the Nike Strategy to Accelerate Research (Nike STAR)™ to specifically fund CMT-related research. The scientists or Principal Investigators conducting research for the Nike STAR initiative have been chosen from an international body of the world’s most accomplished medical pioneers. The Nike STAR program’s unique character stems from the willingness of each and every one of these prominent researchers to come together to advance CMT research as a team, sharing and communicating ideas, discoveries and research.

Background

CMT1A, the most common form of CMT, is caused by a duplication of a gene which causes an overproduction of a protein (PMP22). PMP22 and myelin are made by cells known as Schwann cells. Myelin is the insulation that surrounds the nerve fibers, which are also known as axons. The over-expression of PMP22 causes the deterioration of the myelin sheath that surrounds the axon, ultimately resulting in the deterioration of the axon itself. As a result of this process, vital nerve impulses are no longer able to transmit efficiently, resulting in the weakness and loss of sensation that characterize CMT1A.

Two different medications (vitamin C and a progesterone antagonist, onapristone) have already been shown to reduce PMP22 levels to a more normal expression in laboratory models of CMT1A. Neither has been validated in clinical trials in humans, although trials of vitamin C are underway in several European countries and in the United States (the US trial is funded by the CMTA in partnership with the MDA). The progesterone antagonist (onapristone) used to treat CMT1A in laboratory models isn’t suitable because of its toxicity in humans.

Since there are surely many other potential but undiscovered compounds currently available to lower PMP22 levels and treat CMT1A, our aim is to develop a screening methodology to identify as many compounds simultaneously, in the least amount of time possible. This is feasible with currently available technology through a process known as “high-throughput screening,” in which various compounds are tested using robots and cultured Schwann cells to screen tens of thousands of candidate compounds to determine whether they can lower PMP22 levels.

By partnering with pharmaceutical companies and some of the best Schwann cell scientists in the world, we will endeavor to test hundreds of thousands to millions of compounds. The “hits” generated in this screening process will be validated, through ever more stringent tests, including a laboratory model of CMT1A. The goal is to develop at least two compounds during Phase 1 trials within a three-year period.

This Year's Three-Pronged Research Initiative

In order to reach our ambitious goal of developing compounds that can treat CMT1A, the CMTA is funding the following three projects:

Project 1: Development of a stabilized cell line that expresses PMP22

Using actual Schwann cells, as well as Schwann cells combined with tumor cells (which promote growth), we plan to create a cell line which researchers will use with high-throughput screening to identify which compounds currently in use by drug companies work to diminish the amount of PMP22 in a cell. Thousands of medicines can be placed in tissue culture plates. By utilizing fluorescence or luminescence, researchers are able to observe which medicines dim the fluorescent glow, suggesting that a particular compound is lowering the amount of PMP22 being produced. Since CMT1A involves the overproduction of PMP22, this procedure should quickly produce “candidate” medicines to control that overproduction.

Project 2: Creation of a new laboratory model in which both compounds and PMP22 can be tested at a level closest to human testing.

The creation of this new laboratory model will provide scientists with Schwann cells to test the already available drug compounds as discussed in Project 1, but the animals will also be used to actually test the candidate medicines as they are identified.

Project 3: Characterization of the human PMP22 regions

This project will examine, in detail, the regulation of PMP22 in humans. What is known thus far comes from work with laboratory models. Logically, the next step is to study how the human PMP gene is “turned on” and causes an overexpression of that specific protein in CMT1A.

Following the completion of these projects, the CMTA will aggressively work to pursue any potential treatments arising from these trials, as well as foster new strategies for treating other forms of CMT including 1X, and Types 2 and 4. Initial studies focusing on CMT1A will inevitably be “translational,” directly impacting how we unravel the complexities of and ultimately treatments for other forms of CMT.
A vision of the CMTA is to promote collaborative work on an international level for developing effective therapies for CMT. To this end, an additional goal of the CMTA will be to develop partnerships with organizations such as the NIH and the MDA who share this vision.