title: Fully deleted adenovirus persistently expressing GAA accomplishes long-term skeletal muscle glycogen correction in tolerant and nontolerant GSD-II mice.
abstract: Glycogen storage disease type II (GSD-II) patients manifest symptoms of muscular dystrophy secondary to abnormal glycogen storage in cardiac and skeletal muscles. For GSD-II, we hypothesized that a fully deleted adenovirus (FDAd) vector expressing hGAA via nonviral regulatory elements (PEPCK promoter/ApoE enhancer) would facilitate long-term efficacy and decrease propensity to generate anti-hGAA antibody responses against hepatically secreted hGAA. Intravenous delivery of FDAdhGAA into GAA-tolerant or nontolerant GAA-KO mice resulted in long-term hepatic secretion of hGAA. Specifically, nontolerant mice achieved complete reversal of cardiac glycogen storage and near-complete skeletal glycogen correction for at least 180 days and tolerant mice for minimally 300 days coupled with the preservation of muscle strength. Anti-hGAA antibody levels in both mouse strains were significantly less relative to those previously generated by CMV-driven hGAA expression in nontolerant GAA-KO mice. However, plasma GAA levels decreased in nontolerant GAA-KO mice despite long-term intrahepatic GAA expression from the persistent vector. This intriguing result is discussed in light of other examples of "tolerance" induction by gene-transfer-based approaches.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Kiang
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: Shaoxi
authors.initials: S
authors.lastname: Liao
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.forename: Delila
authors.initials: D
authors.lastname: Serra
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Palmer
authors.forename: Philip
authors.initials: P
authors.lastname: Ng
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004742:Enhancer Elements, Genetic; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006003:Glycogen / Q000378:metabolism*; D006009:Glycogen Storage Disease Type II / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000520:alpha-Glucosidases / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D006003:Glycogen; D000520:alpha-Glucosidases