RESUMEN

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.

Asunto(s)

Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de Homeodominio/efectos de los fármacos , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , MicroARNs/genética , MicroARNs/farmacología , Distrofia Muscular Facioescapulohumeral/tratamiento farmacológico , Adulto , Anciano , Animales , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos , Femenino , Terapia Genética , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares , Distrofia Muscular Facioescapulohumeral/patología , Sistemas de Lectura Abierta/efectos de los fármacos , Interferencia de ARN