Fully Deleted Adenovirus Persistently Expressing GAA Accomplishes Long-Term Skeletal Muscle Glycogen Correction in Tolerant and Nontolerant GSD-II Mice

• Published in: Molecular therapy Vol. 13; no. 1; pp. 127 - 134
• Main Authors: Kiang, Anne, Hartman, Zachary C, Liao, Shaoxi, Xu, Fang, Serra, Delila, Palmer, Donna J, Ng, Philip, Amalfitano, Andrea
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.01.2006
• Subjects: Adenoviridae - genetics; Adenoviruses; alpha-Glucosidases - blood; alpha-Glucosidases - genetics; alpha-Glucosidases - metabolism; Animals; Enhancer Elements, Genetic; Gene therapy; Gene Transfer Techniques; Genetic Vectors; Glycogen - metabolism; Glycogen Storage Disease Type II - genetics; Glycogen Storage Disease Type II - metabolism; Humans; Immune Tolerance; Liver - metabolism; Mice; Mice, Knockout; Muscle, Skeletal - metabolism; Musculoskeletal system; Myocardium - metabolism; Pediatrics; Plasma; Promoter Regions, Genetic; United States > US
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2005.08.006

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.