title: Sustained AAV-mediated dystrophin expression in a canine model of Duchenne muscular dystrophy with a brief course of immunosuppression.
abstract: Adeno-associated virus-based vector (AAV)-mediated gene delivery has been successful in some animal models of human disease such as the mdx mouse model of human Duchenne muscular dystrophy (DMD). However, recent evidence of immune-mediated loss of vector persistence in dogs and humans suggests that immune modulation might be necessary to achieve successful long-term transgene expression in these species. We have previously demonstrated that direct intramuscular injection of AAV2 or AAV6 in wild-type random-bred dogs resulted in a robust immune response to capsid or capsid-associated proteins. We now demonstrate that a brief course of immunosuppression with a combination of anti-thymocyte globulin (ATG), cyclosporine (CSP), and mycophenolate mofetil (MMF) is sufficient to permit long-term and robust expression of a canine micro-dystrophin (c-micro-dys) transgene in the skeletal muscle of a dog model for DMD (canine X-linked muscular dystrophy, or cxmd dog) and that its expression restored localization of components of the dystrophin-associated protein complex at the muscle membrane. This protocol has potential applications to human clinical trials to enhance AAV-mediated therapies.
authors.affiliation: Program in Transplantation Biology, Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Zejing
authors.initials: Z
authors.lastname: Wang
authors.forename: Christian S
authors.initials: CS
authors.lastname: Kuhr
authors.forename: James M
authors.initials: JM
authors.lastname: Allen
authors.forename: Michael
authors.initials: M
authors.lastname: Blankinship
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Chamberlain
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
mesh_terms: D000818:Animals; D000961:Antilymphocyte Serum / Q000494:pharmacology / Q000627:therapeutic use; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D004359:Drug Therapy, Combination; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D007165:Immunosuppression Therapy / Q000379:methods*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000235:genetics / Q000276:immunology / Q000628:therapy; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000961:Antilymphocyte Serum; D016189:Dystrophin; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid