title: Phenotypic improvement of dystrophic muscles by rAAV/microdystrophin vectors is augmented by Igf1 codelivery.
abstract: The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to sarcolemmal instability and enhances the susceptibility of muscle fibers to contraction-induced injury. Various viral vectors have been used to deliver mini- and microdystrophin expression cassettes to muscles of dystrophin-deficient mdx mice, significantly increasing both the morphological and the functional properties of the muscles. However, dystrophin delivery to adult mdx mice has not yielded a complete rescue of the dystrophic phenotype. Here we investigated a novel strategy involving dual gene transfer of recombinant adeno-associated viral vectors expressing either microdystrophin (rAAV-muDys) or a muscle-specific isoform of Igf-1 (rAAV-mIgf-1). Injection of mdx muscles with rAAV-muDys reduced myofiber degeneration and turnover and increased their resistance to mechanical injury, but did not increase muscle mass or force generation. Injection of mdx muscles with rAAV-mIgf-1 led to increased muscle mass, but did not provide protection against mechanical injury or halt myofiber degeneration, leading to loss of the vector over time. In contrast, co-injection of the rAAV-muDys and rAAV-mIgf-1 vectors resulted in increased muscle mass and strength, reduced myofiber degeneration, and increased protection against contraction-induced injury. These results suggest that a dual-gene, combinatorial strategy could enhance the efficacy of gene therapy of DMD.
authors.affiliation: Department of Neurology, Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington School of Medicine, Box 357720, Seattle, WA 98195-7720, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Abmayr
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.forename: James M
authors.initials: JM
authors.lastname: Allen
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Chamberlain
mesh_terms: D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006984:Hypertrophy; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009132:Muscles / Q000473:pathology; D009136:Muscular Dystrophies / Q000628:therapy*; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D016189:Dystrophin; D012333:RNA, Messenger; D012313:RNA; D007334:Insulin-Like Growth Factor I; D004247:DNA