Repeat-selective screening identifies microtubule inhibitors that reduce toxic CUG RNA

Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy. It is caused by a CTG microsatellite expansion in the DMPK gene. Transcription of the CTG repeats gives rise to CUG repeat RNA with a toxic gain-of-function. The toxic CUG RNA sequesters the muscleblind-like (MBNL) family of RNA-binding proteins and disrupts their normal cellular function causing global mis-regulation of RNA processing. We carried out unbiased chemical screening to identify compounds that selectively reduce toxic CUG RNA levels leading to the identification of multiple microtubule inhibitors. Colchicine, and FDA-approved microtubule destabilizing agent was used to treat patient-derived myotubes and the HSALR DM1 transgenic mouse model. Colchicine treatment selectively reduced toxic RNA levels and partially rescued mis-splicing of multiple MBNL-dependent pre-mRNA events with minimal off-target effects on gene expression.