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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 2016,14 May 2019

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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 Final Report, we report on progress for years 1 and 2, as well as our no-cost extension. We will discuss our attempts to complete the original proposed tasks in the Statement of Work and our alternative strategies that we employed to continue moving toward therapeutic development for ALS. Although we made some changes to our research plan, we still expect to identify chemical compounds that will represent lead molecules for therapeutic development of C9FTDALS, the leading genetic cause of ALS, in the coming months and years as we try to find funding to continue this important project.

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  • Medicine and Medical Research

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