A natural microRNA spiked with small molecules to knock down DUX4 in FSHD

Facioscapulohumeral muscular dystrophy (FSHD or FSH) is characterized by an aberrant expression of the DUX4 gene. To prevent it, in a gene silencing approach, a therapeutic avenue consists in specifically binding the messenger RNA of DUX4 to synthetic RNAs of the complementary siRNA or miRNA type. 

In the United States, a team of gene therapy researchers is developing an original alternative. It is based on a natural micro-RNA and on small molecules capable of increasing its expression. According to preclinical results published by the North American team:

  • Among human endogenous microRNAs, miR-675 inhibits DUX4 mRNA and DUX4 protein expression in cellular models of disease;
  • Gene therapy delivering miR-675 using an AAV vector protects muscle in a mouse model from DUX4-induced toxicity;
  • β-estradiol alone, β-estradiol associated with medroxyprogesterone acetate and melatonin are able to increase the expression of miR-675 and thereby inhibit DUX4 in the myotubes of patients with FSH.

This would be the first study demonstrating the effectiveness of small molecules to reversibly repress the gene of a dominantly transmitted disease using an RNA interference mechanism. The authors underline the interest of continuing work on miR-675, whose rate varies from one individual to another, a characteristic which could make this nucleic acid a modifier of the disease. It would also be useful to identify other miRNAs involved in FSH and sensitive to other molecules.


Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy. Saad NY, Al-Kharsan M, Garwick-Coppens SE et al. Nat Commun. 2021 Dec 8;12(1):7128.