title: Therapeutic impact of systemic AAV-mediated RNA interference in a mouse model of myotonic dystrophy.
abstract: RNA interference (RNAi) offers a promising therapeutic approach for dominant genetic disorders that involve gain-of-function mechanisms. One candidate disease for RNAi therapy application is myotonic dystrophy type 1 (DM1), which results from toxicity of a mutant mRNA. DM1 is caused by expansion of a CTG repeat in the 3' UTR of the DMPK gene. The expression of DMPK mRNA containing an expanded CUG repeat (CUG(exp)) leads to defects in RNA biogenesis and turnover. We designed miRNA-based RNAi hairpins to target the CUG(exp) mRNA in the human α-skeletal muscle actin long-repeat (HSA(LR)) mouse model of DM1. RNAi expression cassettes were delivered to HSA(LR) mice using recombinant adeno-associated viral (rAAV) vectors injected intravenously as a route to systemic gene therapy. Vector delivery significantly reduced disease pathology in muscles of the HSA(LR) mice, including a reduction in the CUG(exp) mRNA, a reduction in myotonic discharges, a shift toward adult pre-mRNA splicing patterns, reduced myofiber hypertrophy and a decrease in myonuclear foci containing the CUG(exp) mRNA. Significant reversal of hallmarks of DM1 in the rAAV RNAi-treated HSA(LR) mice indicate that defects characteristic of DM1 can be mitigated with a systemic RNAi approach targeting the nuclei of terminally differentiated myofibers. Efficient rAAV-mediated delivery of RNAi has the potential to provide a long-term therapy for DM1 and other dominant muscular dystrophies.
authors.affiliation: Division of Medical Genetics, Department of Medicine.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Bisset
authors.affiliation: Division of Medical Genetics, Department of Medicine.
authors.forename: Ewa A
authors.initials: EA
authors.lastname: Stepniak-Konieczna
authors.affiliation: Division of Medical Genetics, Department of Medicine.
authors.forename: Maja
authors.initials: M
authors.lastname: Zavaljevski
authors.affiliation: Division of Medical Genetics, Department of Medicine.
authors.forename: Jessica
authors.initials: J
authors.lastname: Wei
authors.affiliation: MEDEX Division, Department of Family Medicine and and.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Carter
authors.affiliation: Department of Neurology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weiss
authors.affiliation: Division of Medical Genetics, Department of Medicine, jrcham@uw.edu.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Chamberlain
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D015870:Gene Expression; D023061:Gene Order; D020868:Gene Silencing; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000628:therapy; D010641:Phenotype; D034622:RNA Interference; D012326:RNA Splicing; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D019076:Transgenes
chemical_list: D004268:DNA-Binding Proteins; C479922:Mbnl1 protein, mouse; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins