# Targeting the PMP22 Protein to Develop Leads Against Charcot-Marie-Tooth Disease

> **NIH NIH R21** · VANDERBILT UNIVERSITY · 2021 · $237,316

## Abstract

Project Summary
Charcot-Marie-Tooth Disease (CMTD) is a debilitating hereditary peripheral neuropathy that afflicts 1:2500
humans. The hallmark of CTMD pathology is severely defective PNS myelin. There is currently no
pharmacological treatment or cure for this disease. Over 75% of all cases of CMTD are caused by
Schwann cell overexpression of wild type (WT) peripheral myelin protein (PMP22) due to trisomy,
underexpression of PMP22 (for the WT/null case), or genetically dominant heterozygous (WT/mutant)
mutations that alter the PMP22 protein sequence. WT PMP22 is known to properly fold and traffic with
only 20% efficiency under healthy conditions. Our driving rationale is that small molecules that tune either
the expression levels or in vivo folding efficiency of PMP22 have the potential to be effective therapeutic
agents. Drugs that reduce expression of the protein are likely to prove effective against the most common
form of CMTD (Type 1A) caused by trisomy-based overexpression. On the other hand, drugs that act as
folding correctors or expression enhancers are likely to prove effective for forms of CMTD caused by
underexpression and/or misfolding of PMP22. The Specific Aims of this project are designed to establish
the foundations for a drug discovery program to develop therapeutic compounds for the most common
forms of Charcot-Marie-Tooth Disease (CMTD), which are caused by genetic variations that impact the
PMP22 gene that encodes peripheral myelin protein 22 (PMP22), a tetraspan membrane protein.
These Aims are:
 Aim 1. Develop a primary assay that can be implemented in high throughput screening (HTS)
mode to identify small molecules that alter the total expression of wild type (WT) and disease mutant
forms of PMP22, or that enhance the cell surface membrane trafficking of the protein.
 Aim 2. Conduct primary screens to discover and characterize lead compounds that modulate total
expression levels of PMP22 and/or that enhance PMP22 cell surface trafficking efficiency. Determine hit
concentration-response (potency) curves.
 Aim 3. Conduct a secondary screen of hits using Schwann cells and test for hit efficacy in a
myelination assay. Conduct biophysical studies to test whether lead compounds act in a way what
involves direct binding to the PMP22 protein and also test for their impact on PMP22 protein stability.
Successful completion of this project will provide a series of lead compounds that will be ready
for future medicinal chemistry optimization of lead compound structures, efficacy testing in
available mouse and rat models of CMTD, and pre-clinical testing.

## Key facts

- **NIH application ID:** 10105584
- **Project number:** 1R21NS119889-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** CHARLES R SANDERS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $237,316
- **Award type:** 1
- **Project period:** 2021-01-20 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105584

## Citation

> US National Institutes of Health, RePORTER application 10105584, Targeting the PMP22 Protein to Develop Leads Against Charcot-Marie-Tooth Disease (1R21NS119889-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10105584. Licensed CC0.

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