Evasion of immune responses to introduced human acid alpha-glucosidase by liver-restricted expression in glycogen storage disease type II.
Glycogen storage disease type II (GSD-II; Pompe disease) is caused by a deficiency of acid alpha-glucosidase (GAA; acid maltase) and manifests as muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. Adeno-associated virus vectors containing either a liver-specific promoter (LSP) (AAV-LSPhGAApA) or a hybrid CB promoter (AAV-CBhGAApA) to drive human GAA expression were pseudotyped as AAV8 and administered to immunocompetent GAA-knockout mice. Secreted hGAA was detectable in plasma between 1 day and 12 weeks postadministration with AAV-LSPhGAApA and only from 1 to 8 days postadministration for AAV-CBGAApA. No anti-GAA antibodies were detected in response to AAV-LSPhGAApA (<1:200), whereas AAV-CBhGAApA provoked an escalating antibody response starting 2 weeks postadministration. The LSP drove approximately 60-fold higher GAA expression than the CB promoter in the liver by 12 weeks following vector administration. Furthermore, the detected cellular immunity was provoked by AAV-CBhGAApA, as detected by ELISpot and CD4+/CD8+ lymphocyte immunodetection. GAA activity was increased to higher than normal and glycogen content was reduced to essentially normal levels in the heart and skeletal muscle following administration of AAV-LSPhGAApA. Therefore, liver-restricted GAA expression with an AAV vector evaded immunity and enhanced efficacy in GSD-II mice.
Franco
Luis M
LM
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Sun
Baodong
B
Yang
Xiaoyi
X
Bird
Andrew
A
Zhang
Haoyue
H
Schneider
Ayn
A
Brown
Talmage
T
Young
Sarah P
SP
Clay
Timothy M
TM
Amalfitano
Andrea
A
Chen
Y T
YT
Koeberl
Dwight D
DD
D000818:Animals; D000917:Antibody Formation; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form / Q000378:metabolism*; D004279:DNA, Viral; D000229:Dependovirus / Q000235:genetics; D004742:Enhancer Elements, Genetic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic; D000520:alpha-Glucosidases / Q000096:biosynthesis* / Q000276:immunology
D004279:DNA, Viral; D006003:Glycogen; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form; D000520:alpha-Glucosidases