title: Correction of glycogen storage disease type II by an adeno-associated virus vector containing a muscle-specific promoter.
abstract: Glycogen storage disease type II (Pompe disease) causes death in infancy from cardiorespiratory failure due to acid alpha-glucosidase (GAA; acid maltase) deficiency. An AAV2 vector pseudotyped as AAV6 (AAV2/6 vector) transiently expressed high-level human GAA in GAA-knockout (GAA-KO) mice without reducing glycogen storage; however, in immunodeficient GAA-KO/SCID mice the AAV2/6 vector expressed high-level GAA and reduced the glycogen content of the injected muscle for 24 weeks. A CD4+/CD8+ lymphocytic infiltrate was observed in response to the AAV2/6 vector in immunocompetent GAA-KO mice. When a muscle-specific creatine kinase promoter was substituted for the CB promoter (AAV-MCKhGAApA), that AAV2/6 vector expressed high-level GAA and reduced glycogen content in immunocompetent GAA-KO mice. Muscle-restricted expression of hGAA provoked only a humoral (not cellular) immune response. Intravenous administration of a high number of particles of AAV-MCKhGAApA as AAV2/7 reduced the glycogen content of the heart and skeletal muscle and corrected individual myofibers in immunocompetent GAA-KO mice 24 weeks postinjection. In summary, persistent correction of muscle glycogen content was achieved with an AAV vector containing a muscle-specific promoter in GAA-KO mice, and this approach should be considered for muscle-targeted gene therapy in Pompe disease.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Baodong
authors.initials: B
authors.lastname: Sun
authors.forename: Haoyue
authors.initials: H
authors.lastname: Zhang
authors.forename: Luis M
authors.initials: LM
authors.lastname: Franco
authors.forename: Talmage
authors.initials: T
authors.lastname: Brown
authors.forename: Andrew
authors.initials: A
authors.lastname: Bird
authors.forename: Ayn
authors.initials: A
authors.lastname: Schneider
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood; D000917:Antibody Formation; D003402:Creatine Kinase / Q000235:genetics*; D052283:Creatine Kinase, MM Form; D004279:DNA, Viral / Q000032:analysis; D000229:Dependovirus / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006003:Glycogen / Q000032:analysis; D006009:Glycogen Storage Disease Type II / Q000235:genetics / Q000628:therapy*; D006801:Humans; D007273:Injections, Intramuscular; D007527:Isoenzymes / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000737:chemistry / Q000201:enzymology*; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000520:alpha-Glucosidases / Q000032:analysis / Q000235:genetics* / Q000276:immunology
chemical_list: D000906:Antibodies; D004279:DNA, Viral; D007527:Isoenzymes; D006003:Glycogen; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form; D000520:alpha-Glucosidases