Small molecule combination therapy for myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is an autosomal dominant, CTG microsatellite expansion disease. 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. Multiple approaches have been developed to target the toxic RNA; these include, but are not limited to, displacing MBNL proteins from the CUG repeats, increasing MBNL protein levels or delivery of exogenous MBNL proteins, and blocking the transcription of the CUG repeats. As proof-of-concept, we studied a combination of two previously characterized small molecules, erythromycin and furamidine, in two DM1 models. Using RNA-seq data in DM1 patient-derived myotubes, additive rescue of mis-splicing was observed with little to no cell toxicity with the combination therapy. In a DM1 mouse model, a combination of erythromycin and the prodrug of furamidine (pafuramidine), administered orally, displayed both additive and synergistic mis-splicing rescue. Gene expression was only modestly affected and over 40% of the genes showing significant expression changes were rescued back toward WT expression levels.