Myotonic dystrophy type 1 (DM1), one of the most common neuromuscular diseases in adults, is characterized by muscle weakness and wasting, myotonia as well as cardiac and cognitive defects. DM1 is an autosomal dominant disorder caused by microsatellite expansions of CTG repeats in the 3’UTR of the DMPK gene, and globally, the size of the expansion correlates with the clinical severity and the age of onset of the disease. Expression of mutant transcripts carrying expanded CUG repeats (CUGexp-RNA) leads to a toxic RNA gain-of-function mechanism. CUGexp-RNA are retained in the nucleus as discrete foci that sequester MBNL RNA-binding factors hampering their functions and resulting on RNA metabolism defects including alternative splicing misregulations. Thus, several splicing changes in DM patients have been associated with clinical symptoms such as myotonia, muscle weakness, insulin resistance, cardiac and cognitive defects.
To date, there is no therapy available for DM1 however several therapeutic approaches are under development. Here, we report a gene therapy strategy to reverse RNA toxicity in DM1 via an engineered RNA-binding protein with high affinity for CUGexp that acts as a decoy to release sequestered endogenous MBNL factors from CUGexp and restore their proper functions. In muscle cells derived form a patient with DM1, we showed that the decoy interferes with CUGexp-RNA, releases MBNL1 from foci and corrects the transcriptomic signature of DM1. Next, we assessed this gene therapy approach in a mouse model of the disease expressing CUGexp-RNA in skeletal muscles. We found that a single local or systemic injection of AAV9 vectors allowing decoy expression leads to long-lasting correction of splicing defects and myotonia in skeletal muscles of DM1 mice. In conclusion, our results support the development of decoy RNA-binding protein with high affinity for CUGexp as an alternate or complementary therapeutic intervention for DM1.