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Chemical Library Screening for Potential Therapeutics Using Novel Cell-Based Models of ALS

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Technical Report,15 May 2017,14 May 2018

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Southern Illinois University Carbondale United States

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The leading cause of inherited amyotrophic lateral sclerosis ALS and frontotemporal dementia FTD is a microsatellite repeat expansion in the C9ORF72 gene. This disorder is referred to as C9FTDALS. The disease mechanisms are still poorly understood. However, it is clear that the repeat expansion sequence is made into RNA that can aggregate in the nucleus of patient cells. The expansion RNA can also be translated into repetitive polypeptides in the cytoplasm of patient cells. These two processes are expected to play key roles in the initiation and progression of disease at the molecular and cellular level. Drugs that can block or reverse these processes would hold promise as therapeutics to treat C9FTDALS. The overall goal of this project is to develop new cell-based models of C9FTDALS that recapitulate these two disease processes. RNA foci and repetitive polypeptides will be visible through fluorescence microscopy. These cells will then be used for high throughput chemical library screening to identify and characterize molecules with therapeutic potential. For this Annual Technical Progress Report, we report on progress for year 2 according to the proposed Statement of Work. We have largely completed Major Task 1,preparation of custom expression vectors and model cell lines. We have obtained a no-cost extension and made minor adjustments to our research plan to accommodate completion of Major Tasks 2 and 3 in the remaining year of the project. We expect to identify chemical compounds that will represent lead molecules for therapeutic development of C9FTDALS, the leading genetic cause of ALS.

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  • Medicine and Medical Research

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