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. miRNAs are single-stranded, small, non-coding RNA of 22 nucleotides that play important roles as endogenous gene regulators by mediating translation repression or promoting degradation of target mRNA. While the normal expression and function of miRNAs are vital for physiological processes, aberrant expression of miRNAs has been proven to be closely related to the occurrence of various cancers. Perturbation of endogeneous miRNAs help to study the function of specific miRNAs and hold the potential for therapeutics.
RNA interference (RNAi) is one powerful approach to inhibit DUX4, and previously described a RNAi gene therapy to achieve DUX4 silencing in FSHD cells and mice using engineered microRNAs. This paper reported 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, This research shows that three known miR-675-upregulating small molecules inhibit DUX4 and DUX4-activated FSHD biomarkers in FSHD patient-derived myotubes.
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References:
Saad Nizar Y,Al-Kharsan Mustafa,Garwick-Coppens Sara E et al. Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy.[J] .Nat Commun, 2021, 12: 7128.