Researchers at Vanderbilt University have made significant progress in the development of small molecules aimed at treating Charcot-Marie-Tooth disease types caused by mutations in the PMP22 gene, which include CMT1A, CMT1E and hereditary neuropathy with liability to pressure palsies, also known as HNPP.

The Basics of the PMP22 Problem – Too Much Versus Too Little

PMP22 gene mutations that lead to an overproduction of PMP22 cause CMT1A, while mutations that lead to underproduction cause HNPP, emphasizing the importance of having the right balance of PMP22 protein in Schwann cells to support healthy myelination. Additionally, mutations in PMP22 that cause the protein to accumulate inside the cell or to not function properly, cause CMT1E.

Identifying drugs that can restore PMP22 levels and function to healthy levels serves as a major therapeutic goal for each of these subtypes. This cutting-edge drug discovery project, funded by CMTRF, focuses on identifying small molecule compounds that alter the levels of PMP22 in Schwann cells to restore proper nerve function for these specific types of CMT.

Finding Small Molecules That can Regulate PMP22

We previously reported that the researchers had screened a library of over 20,000 small molecules and identified several that showed promising activity and warranted further investigation.

In the second year of this project, they conducted additional evaluations to further assess the potency and efficacy of these compounds in Schwann cells. They also developed and tested new versions to identify additional candidate compounds with greater effects on altering PMP22 production or trafficking.

From 20,000 Options Down to 3

These studies revealed three candidate compounds that significantly alter PMP22 levels. Of these, two reduce PMP22 levels, highlighting their potential for CMT1A and CMT1E, where PMP22 is overproduced or forms intracellular aggregates. The third candidate increases PMP22 levels, making it a possible solution for HNPP, where PMP22 is underproduced. Importantly, all three candidate compounds demonstrated no signs of Schwann cell toxicity, making them strong prospects for further testing, which will include testing their ability to correct disease symptoms in tissue and mouse models.

Interestingly, the researchers identified that all three molecules do not directly bind to PMP22, meaning they reduce PMP22 levels indirectly — likely by interacting with another target that influences PMP22 expression.

Fine-Tuning the Molecular Mechanism so we can Test More Deeply

As the project moves forward, the team will continue to study the molecular mechanisms behind these compounds, with plans to optimize their effectiveness and assess their ability to promote nerve cell myelination. Additional screening efforts are also underway to discover more potential candidate compounds.

CMTRF is encouraged by the progress so far and eagerly anticipates future results. For more information on this CMTRF-funded project, click here.