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

Mol Ther. 2005 Nov;12(5):876-84. doi: 10.1016/j.ymthe.2005.04.024. Epub 2005 Jul 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody Formation
  • Creatine Kinase
  • Creatine Kinase, MM Form / metabolism*
  • DNA, Viral
  • Dependovirus / genetics
  • Enhancer Elements, Genetic
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors* / administration & dosage
  • Genetic Vectors* / genetics
  • Glycogen / metabolism
  • Glycogen Storage Disease Type II / immunology
  • Glycogen Storage Disease Type II / metabolism*
  • Glycogen Storage Disease Type II / therapy
  • Humans
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Plasmids / genetics
  • Promoter Regions, Genetic
  • alpha-Glucosidases / biosynthesis*
  • alpha-Glucosidases / immunology


  • DNA, Viral
  • Glycogen
  • Creatine Kinase
  • Creatine Kinase, MM Form
  • alpha-Glucosidases