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.