! Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder that that predominately affects adults over the age of 50. Individuals afflicted with FXTAS develop tremor, ataxia, Parkinson-like symptoms, and slowly lose their cognitive abilities to the point that they are completely dependent on others for care. Currently, there is no cure. Therefore, there is a strong need to discover first-in-class drug treatments capable of preventing and/or reversing FXTAS disease progression. FXTAS is a trinucleotide repeat disorder caused by premutations in the fragile X mental retardation 1 (FMR1) gene. RNA gain-of-function toxicity from the expanded trinucleotide tracts in FMR1 is thought to be the primary cause of FXTAS pathology. In the nucleus, expanded trinucleotide tracts form RNA aggregates that sequester RNA-binding proteins and splicing factors from normal cellular functions and trigger cell degeneration. Therefore, the discovery of small molecules that disrupt the nuclear formation of toxic RNA aggregates would be highly desirable as potential therapeutics for FXTAS. In order to discover ribonuclear foci inhibitors, high-throughput assays capable of providing a convenient readout for RNA foci formation are needed. Current techniques suffer from major limitations that make them difficult to use and produce results of dubious validity. In this proposal, we will develop a RNA-based trinucleotide repeat RNA reporter system that will enable us to detect the formation of CGG150 RNA foci in a cellular environment and facilitate the screening of small molecules libraries for drugs that inhibit toxic CGG150 RNA aggregation. !

Public Health Relevance

Fragile X-associated tremor/ataxia syndrome (FXTAS) a progressive neurodegenerative disorder that affects about 1 in 3,000 men and 1 in 5,200 women in the general population. It has been shown that toxic aggregations of expanded trinucleotide repeat transcripts alter developmentally regulated splicing and trigger cell death. Therefore, this project will develop a cell-based trinucleotide repeat reporter that measure toxic RNA foci formation in the nucleus and enable cell-based HTS screen for the discovery of new FXTAS drugs.

National Institute of Health (NIH)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Brooks, Pj
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Lucerna, Inc.
New York
United States
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