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RNA interference (RNAi) offers a promising therapeutic approach for dominant genetic disorders that involve gain-of-function mechanisms. One candidate disease for RNAi therapy application is myotonic dystrophy type 1 (DM1), which results from toxicity of a mutant mRNA. DM1 is caused by expansion of a CTG repeat in the 3′ UTR of the  DMPK  gene. The expression of  DMPK  mRNA containing an expanded CUG repeat (CUG exp ) leads to defects in RNA biogenesis and turnover. We designed miRNA-based RNAi hairpins to target the CUG exp  mRNA in the human  α-skeletal muscle actin  long-repeat ( HSA  LR ) mouse model of DM1. RNAi expression cassettes were delivered to  HSA  LR  mice using recombinant adeno-associated viral (rAAV) vectors injected intravenously as a route to systemic gene therapy. Vector delivery significantly reduced disease pathology in muscles of the  HSA  LR  mice, including a reduction in the CUG exp  mRNA, a reduction in myotonic discharges, a shift toward adult pre-mRNA splicing patterns, reduced myofiber hypertrophy and a decrease in myonuclear foci containing the CUG exp  mRNA. Significant reversal of hallmarks of DM1 in the rAAV RNAi-treated  HSA  LR  mice indicate that defects characteristic of DM1 can be mitigated with a systemic RNAi approach targeting the nuclei of terminally differentiated myofibers. Efficient rAAV-mediated delivery of RNAi has the potential to provide a long-term therapy for DM1 and other dominant muscular dystrophies.

Therapeutic impact of systemic AAV-mediated RNA interference in a mouse model of myotonic dystrophy