title: Intra-amniotic rAAV-mediated microdystrophin gene transfer improves canine X-linked muscular dystrophy and may induce immune tolerance.
abstract: Duchenne muscular dystrophy (DMD) is a severe congenital disease due to mutations in the dystrophin gene. Supplementation of dystrophin using recombinant adenoassociated virus vector has promise as a treatment of DMD, although therapeutic benefit of the truncated dystrophin still remains to be elucidated. Besides, host immune responses against the vector as well as transgene products have been denoted in the clinical gene therapy studies. Here, we transduced dystrophic dogs fetuses to investigate the therapeutic effects of an AAV vector expressing microdystrophin under conditions of immune tolerance. rAAV-CMV-microdystrophin and a rAAV-CAG-luciferase were injected into the amniotic fluid surrounding fetuses. We also reinjected rAAV9-CMV-microdystrophin into the jugular vein of an infant dystrophic dog to induce systemic expression of microdystrophin. Gait and cardiac function significantly improved in the rAAV-microdystrophin-injected dystrophic dog, suggesting that an adequate treatment of rAAV-microdystrophin with immune modulation induces successful long-term transgene expression to analyze improved dystrophic phenotype.
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hayashita-Kinoh
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yugeta
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nitahara-Kasahara
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Chiyo
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
mesh_terms: D000650:Amnion; D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004283:Dog Diseases / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D004285:Dogs; D016189:Dystrophin / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D040181:Genetic Diseases, X-Linked; D015316:Genetic Therapy; D007108:Immune Tolerance / Q000235:genetics*; D008297:Male; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D010641:Phenotype; D012129:Respiratory Function Tests
chemical_list: D016189:Dystrophin