Drug Screening Assays for Charcot-Marie-Tooth Disease

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DESCRIPTION (provided by applicant): Hereditary peripheral neuropathies (also known as hereditary motor sensory neuropathies, HMSN) are among the most common genetic diseases affecting the nervous system. The mildest form of human peripheral neuropathy, Charcot-Marie- Tooth (CMT) disease, causes progressive deterioration of both motor and sensory nerves, muscular atrophy, and chronic pain/fatigue in affected individuals. A majority of inherited peripheral myelinopathies are caused by duplication of a critical myelin gene, Peripheral Myelin Protein 22 (PMP22), which is classified as CMT1A. Therefore, one of the most straightforward avenues for treating this inherited myelinopathy is to achieve a relatively subtle (<2-fold) change in gene regulation. Recent proof-of-principle studies using candidate compounds to reduce PMP22 expression levels have shown beneficial effects in rodent models of CMT1A. However, these agents have not yet been shown to be effective in clinical trials, and therefore it is criticl to develop effective screening tools that can be used to identify compounds that can achieve a therapeutic reduction in PMP22 levels. Our recent studies of PMP22 regulation have elucidated novel regulatory elements in this gene, and the goal of this proposal is to design and functionally validate novel assays to identify small molecules that reduce PMP22 expression. We propose to utilize a novel technology involving custom zinc finger nucleases, which will allow us to embed a series of orthologous reporters in the native Pmp22 locus. The assays will create a series of complementary assays for use in both primary and secondary screening assays. A series of validation assays are proposed to determine if the reporter assays are appropriately regulated, and such assays will be adapted for high throughput screening at the NIH Chemical Genomics Center. PUBLIC HEALTH RELEVANCE: Relevance One of the most common inherited diseases affecting the nervous system is Charcot-Marie-Tooth disease, affecting approximately 1 in 3000 individuals. The most common cause of this disease is a duplication of the PMP22 gene (resulting in CMT1A), but no effective therapies have yet been developed to prevent the progressive deterioration the protective myelin sheath of peripheral nerves. This proposal is designed to create novel tools for small molecule screening aimed at developing novel treatments for CMT1A. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.