Screening of small molecules and lead identification against CAG repeat RNA for the treatment of Huntington’s disease and spinocerebellar ataxia

Abstract

Huntington's disease (HD) is a severe neurodegenerative condition caused by the expansion of CAG repeats in the HTT gene. This expansion leads to the formation of mutant huntingtin proteins, which aggregate and cause cellular toxicity. HD predominantly affects the striatum, particularly the caudate nucleus and putamen, resulting in the degeneration of GABAergic medium spiny neurons. These pathological changes are accompanied by a decrease in GABA and substance P levels, as well as a reduction in dopamine receptor density. Recent therapeutic research has shifted towards targeting RNA to mitigate the pathogenesis of HD. This study focuses on the screening of FDA-approved small molecules for their potential to bind with CAG repeat sequences and alleviate toxicity caused by CAG repeat sequences. Biophysical analyses identified molecule D25 as having specificity and selectivity towards RNA motifs containing CAG repeats. Further experimentation confirmed D25's efficacy in reducing polyglutamine protein formation through cell-based studies and neurobehavioral improvement in in-vivo models. Thus, D25 can be used as a potential therapeutic drug against neurological diseases caused due to CAG repeat expansion such as HD and SCA. This approach could pave the way for developing targeted and effective treatments for HD and similar trinucleotide repeat disorders. Keywords: Huntington’s Disease, CAG, Small Molecules, HTT gene, PolyQ