Evasion of immune responses to introduced human acid alpha-glucosidase by liver-restricted expression in glycogen storage disease type II.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Franco, LM; Sun, B; Yang, X; Bird, A; Zhang, H; Schneider, A; Brown, T; Young, SP; Clay, TM; Amalfitano, A; Chen, YT; Koeberl, DD

Published Date

  • November 2005

Published In

Volume / Issue

  • 12 / 5

Start / End Page

  • 876 - 884

PubMed ID

  • 16005263

International Standard Serial Number (ISSN)

  • 1525-0016

Digital Object Identifier (DOI)

  • 10.1016/j.ymthe.2005.04.024


  • eng

Conference Location

  • United States