Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affectivecarriers of premutation forms of the FMR1 gene. FXTAS results in progressive development of tremor, ataxiaand neuropsychological problems, including anxiety, memory impairment and dementia. Both the gene andthe pathogenic trigger (RNA toxicity) responsible for FXTAS are known; therefore, this disorder represents apromising candidate for development of targeted gene therapies. Development of an effective therapyrequires a thorough understanding the cellular mechanisms of the disease, identification of molecular targetsfor therapy, and development of novel therapeutics that can reach those targets. Project 2 proposes todevelop valid mouse models of FXTAS that will allow us, in concert with Project 1, 3 and 4, to systematicallyexplore the underlying disease mechanisms of FXTAS and to identify molecular targets for new therapies.Specifically, we will develop and use transgenic mice that are constructed to model the gene mutation thatcauses FXTAS (i.e., expanded CGG trinucleotide repeat). We will then use these mice to (1) define criticalperiods in development for disease onset, (2) identify therapeutic windows for treatment, (3) establish thepotential for halting or reversing FXTAS by targeted gene therapies, and (4) test novel therapeutics in micefor their potential to prevent or reverse the development of FXTAS. We will use our existing knock-in micewith expanded CGG trinucleotide .repeats to study the development of disease in mice, and to test novelgene-targeted (i.e., antisense DMA, RNAi) and pharmacological treatments (e.g., lithium, memantine).Additional inducible (tet-on) transgenic mice models will be developed that will enable us to turn off activationof the mutant CGG trinucleotide repeat during development to establish when suppression of abnormal geneexpression can halt or reverse disease progression, as well as identify the specific cell types andmechanisms that cause FXTAS. This project, in concert with the other projects within this Consortium, willgenerate the essential knowledge about the causes of and potential treatments for FXTAS that will providethe foundation for the development of treatments that can halt or reverse the disease.
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