Intra-Amniotic rAAV-Mediated Microdystrophin Gene Transfer Improves Canine X-Linked Muscular Dystrophy and May Induce Immune Tolerance
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 eluci...
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Veröffentlicht in: | Molecular therapy 2015-04, Vol.23 (4), p.627-637 |
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description | 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. |
doi_str_mv | 10.1038/mt.2015.5 |
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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.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2015.5</identifier><identifier>PMID: 25586688</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adeno-associated virus ; Amnion ; Animals ; Dependovirus - genetics ; Dog Diseases - genetics ; Dog Diseases - immunology ; Dog Diseases - therapy ; Dogs ; Dystrophin - genetics ; Female ; Fetuses ; Gait ; Gene therapy ; Gene Transfer Techniques ; Genetic Diseases, X-Linked ; Genetic Therapy ; Genomes ; Genotype & phenotype ; Immune Tolerance - genetics ; Male ; Muscle function ; Muscular dystrophy ; Muscular Dystrophy, Animal - genetics ; Muscular Dystrophy, Animal - immunology ; Muscular Dystrophy, Animal - therapy ; Musculoskeletal system ; Mutation ; Original ; Phenotype ; Respiratory Function Tests ; Umbilical cord ; Vectors (Biology)</subject><ispartof>Molecular therapy, 2015-04, Vol.23 (4), p.627-637</ispartof><rights>2015 The American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group Apr 2015</rights><rights>Copyright © 2015 The American Society of Gene & Cell Therapy 2015 The American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c546t-896022b5afc5938d41ef3d3e5ade97e5ec3bde6bec5e6ec6c5f038038dfdc4383</citedby><cites>FETCH-LOGICAL-c546t-896022b5afc5938d41ef3d3e5ade97e5ec3bde6bec5e6ec6c5f038038dfdc4383</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395797/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1791388094?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25586688$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hayashita-Kinoh, Hiromi</creatorcontrib><creatorcontrib>Yugeta, Naoko</creatorcontrib><creatorcontrib>Okada, Hironori</creatorcontrib><creatorcontrib>Nitahara-Kasahara, Yuko</creatorcontrib><creatorcontrib>Chiyo, Tomoko</creatorcontrib><creatorcontrib>Okada, Takashi</creatorcontrib><creatorcontrib>Takeda, Shin'ichi</creatorcontrib><title>Intra-Amniotic rAAV-Mediated Microdystrophin Gene Transfer Improves Canine X-Linked Muscular Dystrophy and May Induce Immune Tolerance</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>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.</description><subject>Adeno-associated virus</subject><subject>Amnion</subject><subject>Animals</subject><subject>Dependovirus - genetics</subject><subject>Dog Diseases - genetics</subject><subject>Dog Diseases - immunology</subject><subject>Dog Diseases - therapy</subject><subject>Dogs</subject><subject>Dystrophin - genetics</subject><subject>Female</subject><subject>Fetuses</subject><subject>Gait</subject><subject>Gene therapy</subject><subject>Gene Transfer Techniques</subject><subject>Genetic Diseases, X-Linked</subject><subject>Genetic Therapy</subject><subject>Genomes</subject><subject>Genotype & phenotype</subject><subject>Immune Tolerance - genetics</subject><subject>Male</subject><subject>Muscle function</subject><subject>Muscular dystrophy</subject><subject>Muscular Dystrophy, Animal - 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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.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>25586688</pmid><doi>10.1038/mt.2015.5</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adeno-associated virus Amnion Animals Dependovirus - genetics Dog Diseases - genetics Dog Diseases - immunology Dog Diseases - therapy Dogs Dystrophin - genetics Female Fetuses Gait Gene therapy Gene Transfer Techniques Genetic Diseases, X-Linked Genetic Therapy Genomes Genotype & phenotype Immune Tolerance - genetics Male Muscle function Muscular dystrophy Muscular Dystrophy, Animal - genetics Muscular Dystrophy, Animal - immunology Muscular Dystrophy, Animal - therapy Musculoskeletal system Mutation Original Phenotype Respiratory Function Tests Umbilical cord Vectors (Biology) |
title | Intra-Amniotic rAAV-Mediated Microdystrophin Gene Transfer Improves Canine X-Linked Muscular Dystrophy and May Induce Immune Tolerance |
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