title: Impact of humoral immune response on distribution and efficacy of recombinant adeno-associated virus-derived acid alpha-glucosidase in a model of glycogen storage disease type II.
abstract: Glycogen storage disease type II (GSDII) is a lysosomal storage disease caused by a deficiency in acid alpha-glucosidase (GAA), and leads to cardiorespiratory failure by the age of 2 years. In this study, we investigate the impact of anti-GAA antibody formation on cross-correction of the heart, diaphragm, and hind-limb muscles from liver-directed delivery of recombinant adeno-associated virus (rAAV)5- and rAAV8-GAA vectors. GAA(-/-) mice receiving 1 x 10(12) vector genomes of rAAV5- or rAAV8-DHBV-hGAA were analyzed for anti-GAA antibody response, GAA levels, glycogen reduction, and contractile function. We demonstrate that restoration of GAA to the affected muscles is dependent on the presence or absence of the antibody response. Immune-tolerant mice had significantly increased enzyme levels in the heart and skeletal muscles, whereas immune-responsive mice had background levels of GAA in all tissues except the diaphragm. The increased levels of activity in immune-tolerant mice correlated with reduced glycogen in the heart and diaphragm and, overall, contractile function of the soleus muscle was significantly improved. These findings highlight the importance of the immune response to rAAV-encoded GAA in correcting GSDII and provide additional understanding of the approach to treatment of GSDII.
authors.affiliation: Department of Pediatrics, and Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610, USA. cresawn@gtc.ufl.edu
authors.forename: Kerry O
authors.initials: KO
authors.lastname: Cresawn
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Fraites
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Mark
authors.initials: M
authors.lastname: Atkinson
authors.forename: Melissa
authors.initials: M
authors.lastname: Lewis
authors.forename: Stacy
authors.initials: S
authors.lastname: Porvasnik
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Cathryn
authors.initials: C
authors.lastname: Mah
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood; D000229:Dependovirus / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005087:Glucan 1,4-alpha-Glucosidase / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000276:immunology* / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D000520:alpha-Glucosidases
chemical_list: D000911:Antibodies, Monoclonal; D006003:Glycogen; D000520:alpha-Glucosidases; D005087:Glucan 1,4-alpha-Glucosidase