Objective: Myotonic dystrophy type 1 (DM1) is caused by the expansion of a CTG repeat in the 3' untranslated region of DMPK. The transcripts containing an expanded CUG repeat (CUG (exp)) result in a toxic gain-of-function by forming ribonuclear foci that sequester the alternative splicing factor muscleblind-like 1 (MBNL1). Although several small molecules reportedly ameliorate RNA toxicity, none are ready for clinical use because of the lack of safety data. Here, we undertook a drug-repositioning screen to identify a safe and effective small molecule for upcoming clinical trials of DM1.
Methods: We examined the potency of small molecules in inhibiting the interaction between CUG (exp) and MBNL1 by in vitro sequestration and fluorescent titration assays. We studied the effect of lead compounds in DM1 model cells by evaluating foci reduction and splicing rescue. We also tested their effects on missplicing and myotonia in DM1 model mice.
Results: Of the 20 FDA-approved small molecules tested, erythromycin showed the highest affinity to CUG (exp) and a capacity to inhibit its binding to MBNL1. Erythromycin decreased foci formation and rescued missplicing in DM1 cell models. Both systemic and oral administration of erythromycin in the DM1 model mice showed splicing reversal and improvement of myotonia with no toxicity. Long-term oral administration of erythromycin at the dose used in humans also improved the splicing abnormality in the DM1 model mice.
Interpretation: Oral erythromycin treatment, which has been widely used in humans with excellent tolerability, may be a promising therapy for DM1.