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

Author

Listed:
  • Nizar Y. Saad

    (Center for Gene Therapy, the Abigail Wexner Research Institute at Nationwide Children’s Hospital)

  • Mustafa Al-Kharsan

    (Center for Gene Therapy, the Abigail Wexner Research Institute at Nationwide Children’s Hospital
    University of New Mexico Health Sciences Center)

  • Sara E. Garwick-Coppens

    (Center for Gene Therapy, the Abigail Wexner Research Institute at Nationwide Children’s Hospital)

  • Gholamhossein Amini Chermahini

    (Center for Gene Therapy, the Abigail Wexner Research Institute at Nationwide Children’s Hospital)

  • Madison A. Harper

    (Center for Gene Therapy, the Abigail Wexner Research Institute at Nationwide Children’s Hospital)

  • Andrew Palo

    (Center for Gene Therapy, the Abigail Wexner Research Institute at Nationwide Children’s Hospital)

  • Ryan L. Boudreau

    (Carver College of Medicine, University of Iowa)

  • Scott Q. Harper

    (Center for Gene Therapy, the Abigail Wexner Research Institute at Nationwide Children’s Hospital
    The Ohio State University College of Medicine)

Abstract

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.

Suggested Citation

  • Nizar Y. Saad & Mustafa Al-Kharsan & Sara E. Garwick-Coppens & Gholamhossein Amini Chermahini & Madison A. Harper & Andrew Palo & Ryan L. Boudreau & Scott Q. Harper, 2021. "Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27430-1
    DOI: 10.1038/s41467-021-27430-1
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