Targeting r(CGG) repeats with small molecule: a therapeutic approach for FXTAS

Abstract

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), a nucleotide repeat expansion disorder, arises from CGG repeat expansions in the 5’ UTR of the FMR1 gene, leading to RNA foci formation and toxic protein aggregation via RAN translation. These fundamental mechanisms often lead to a series of consequences, including splicing defects, neuroinflammation, mitochondrial dysfunction, impaired autophagy, and neuronal cell death. Targeting toxic RNA repeats offers a promising therapeutic strategy. In this study, we identified Celecoxib, a selective COX-2 inhibitor, as a potential treatment for FXTAS. At first, we utilized various biophysical assays and molecular docking to confirm Celecoxib's strong binding affinity towards the r(CGG)exp RNA. Further studies in the cellular model demonstrated the potency of Celecoxib in reducing toxic protein aggregates and improving splicing defects. Notably, it significantly reduces FMR1PolyG aggregates in the Drosophila FXTAS model, leading to improved locomotor impairments and mitigation of associated pathological consequences, including neuroinflammation, mitochondrial dysfunction, impaired autophagy and neuronal cell death. Moreover, Celecoxib treatment significantly extends the lifespan of the flies. Along with that, Celecoxib also exhibit significant effect in the muscles of Drosophila expressing (CGG)90. There, these results collectively support the therapeutic potential of repurposing Celecoxib for the treatment of FXTAS. Keywords: FXTAS, FMR1PolyG, r(CGG)exp, Celecoxib, Drug Repurposing, Trinucleotide repeats.