Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG-repeat expansion in the huntingin (HTT) gene, resulting in expression of the aberrant and cytotoxic Huntingtin protein. Various strategies aim to reduce the cytotoxic protein by degrading the mutant RNA transcript using antisense oligonucleotides (ASOs) and RNA interference (RNAis), but they suffer from off-target effects and poor absorptivity. To address this, we present a high-throughput cellular assay to screen small molecule therapeutics that selectively inhibits mutant HTT expression by targeting the pathogenic RNA transcript. As opposed to ASOs or RNAis, small molecules offer improved bioavailability and selectivity, making them attractive therapeutic candidates. To validate our assay, a known CAG-repeat RNA targeting compound myricetin was used as a positive control, verifying inhibition of protein expression. Furthermore, this assay led to the discovery of a new small molecule that displayed both superior activity and selectivity to myricetin in lowering mutant HTT over wildtype HTT. Beyond HD, this assay could potentially provide a platform for discovering RNA-targeting small molecule therapeutics for other trinucleotide repeat expansion disorders as well.
Kraichely et al. (Sun,) studied this question.