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

Abstract

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.

• Authors: Luis M Franco, Baodong Sun, Xiaoyi Yang, Andrew Bird, Haoyue Zhang, Ayn Schneider, Talmage Brown, Sarah P Young, Timothy M Clay, Andrea Amalfitano, Y T Chen, Dwight D Koeberl
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 12 Issue 5 Pg. 876-84 (Nov 2005) ISSN: 1525-0016 [Print] United States
• PMID: 16005263 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, genetics)
• Glycogen (metabolism)
• Glycogen Storage Disease Type II (immunology, metabolism, therapy)
• Humans
• Liver (metabolism)
• Mice
• Mice, Knockout
• Muscle, Skeletal (metabolism)
• Plasmids (genetics)
• Promoter Regions, Genetic
• alpha-Glucosidases (biosynthesis, immunology)