title: AAV6-mediated systemic shRNA delivery reverses disease in a mouse model of facioscapulohumeral muscular dystrophy.
abstract: Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans.
authors.affiliation: Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Sergia
authors.initials: S
authors.lastname: Bortolanza
authors.forename: Alessandro
authors.initials: A
authors.lastname: Nonis
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Simona
authors.initials: S
authors.lastname: Maciotta
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sitia
authors.forename: Jessica
authors.initials: J
authors.lastname: Wei
authors.forename: Yvan
authors.initials: Y
authors.lastname: Torrente
authors.forename: Clelia
authors.initials: C
authors.lastname: Di Serio
authors.forename: Joel R
authors.initials: JR
authors.lastname: Chamberlain
authors.forename: Davide
authors.initials: D
authors.lastname: Gabellini
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D016601:RNA-Binding Proteins; D013997:Time Factors; D014161:Transduction, Genetic
chemical_list: C101270:FRG1 protein, human; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins