Therapeutic exploration of FDA-approved small molecules for fragile x-associated tremor/ataxia syndrome (FXTAS)

Abstract

From a drug repurposing perspective, targeting neurological disorders like Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) offers both urgency and opportunity. FXTAS, a late-onset neurodegenerative disorder caused by CGG trinucleotide repeat expansion in the FMR1 gene, remains without an effective treatment. The toxic RNA gain-of- function from expanded repeats leads to RNA foci formation, splicing defects, and polyglycine (FMRpolyG) protein aggregation, contributing to progressive neuronal dysfunction. This thesis explores the repurposing of FDA-approved small molecules to selectively bind r(CGG)exp RNA and mitigate its downstream pathological effects. Using a multifaceted approach, the project combined biophysical studies, cell-based assays, and an in vivo Drosophila melanogaster model to evaluate therapeutic efficacy. Biophysical characterization revealed a strong and specific interaction between the candidate molecule and CGG repeat RNA, altering its structure and reducing RNA-protein complex formation. In HEK-293 and COS-7 cells expressing expanded CGG repeats, the compound demonstrated promising cellular rescue, diminishing RNA foci, correcting splicing errors, and reducing FMR polyG aggregates.