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; Scott Q Harper

doi:10.1038/s41467-021-27430-1

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

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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

Nature communications, Vol.12(1), 7128

12/08/2021

DOI: 10.1038/s41467-021-27430-1

PMCID: PMC8654987

PMID: 34880230

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Abstract

AbstractFacioscapulohumeral 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.

Details

Title: Subtitle: Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy
Creators: Nizar Y Saad
Mustafa Al-Kharsan
Sara E Garwick-Coppens
Gholamhossein Amini Chermahini
Madison A Harper
Andrew Palo
Ryan L Boudreau
Scott Q Harper
Resource Type: Journal article
Publication Details: Nature communications, Vol.12(1), 7128
DOI: 10.1038/s41467-021-27430-1
PMID: 34880230
PMCID: PMC8654987
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Language: English
Date published: 12/08/2021
Academic Unit: Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984201432702771

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