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

Nizar Y. Saad, Mustafa Al-Kharsan, Sara E. Garwick-Coppens, Gholamhossein Amini Chermahini, Madison A. Harper, Andrew Palo, Ryan L. Boudreau and Scott Q. Harper ()
Additional contact information
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-27430-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27430-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-27430-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().