CAG repeat-selective compunds reduce abundance of expanded CAG RNAs in patient and murine models of SCAs II

Spinocerebellar ataxias (SCAs) are a genetically heterogenous group of >40 devastating neurodegenerative conditions for which clinical care currently focuses on managing symptoms. Across these diseases there is a large unmet need for therapies that address underlying disease mechanisms. In this study, we utilised the shared CAG repeat expansion mutation causative for a large subgroup of SCAs, to develop a novel disease-independent and mechanism agnostic small molecule screening approach to identify compounds with therapeutic potential across CAG SCAs. Using this screening approach, we identified the FDA approved microtubule inhibitor Colchicine and a novel CAG-repeat binding compound that reduce expression of disease associated transcripts across SCA1, 3 and 7 patient derived fibroblast lines and the Atxn1154Q/2Q SCA1 mouse model in a repeat selective manner. Furthermore, we demonstrate that our lead candidate rescues dysregulated alternative splicing in Atxn1154Q/2Q mice. This work provides the first example of small molecules capable of targeting the underlying mechanism of disease across multiple CAG SCAs. Overall design: SCA1 knock-in mice were treated via intraperitoneal injection with either DMSO alone (4 mice) or Hit 2 dissvolved in DMSO (4 mice) along with 4 wild-type mice also injected with DMSO. After treatments the cerebella were removed and RNA extracted for RNA-seq.