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.
Charcot-Marie-Tooth Disease (CMTD) is a peripheral neuropathy and afflicts roughly 1 out of every 2500 people and for which there is no cure or therapeutic drug. The most common forms of CMTD are caused by genetic defects affecting the protein peripheral myelin protein 22 (PMP22). The goal of this project is to discover therapeutic lead small molecules that alter the expression level of the PMP22 protein or that enhance its cell surface trafficking, leading to increased functional PMP22 and reducing the amount of misfolded protein.