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Facioscapulohumeral muscular dystrophy (FSHD) is a potentially devastating myopathy caused by de-repression of the  DUX4  gene in skeletal muscles. Effective therapies will likely involve  DUX4  inhibition. RNA interference (RNAi) is one powerful approach to inhibit  DUX4 , and we previously described a RNAi gene therapy to achieve  DUX4  silencing in FSHD cells and mice using engineered microRNAs. Here we report a strategy to direct RNAi against  DUX4  using the natural microRNA  miR-675 , which is derived from the lncRNA  H19 . Human  miR-675  inhibits  DUX4  expression and associated outcomes in FSHD cell models. In addition,  miR-675  delivery using gene therapy protects muscles from DUX4-associated death in mice. Finally, we show that three known  miR-675 -upregulating small molecules inhibit  DUX4  and DUX4-activated FSHD biomarkers in FSHD patient-derived myotubes. To our knowledge, this is the first study demonstrating the use of small molecules to suppress a dominant disease gene using an RNAi mechanism.

Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy