Correction of glycogen storage disease type II by an adeno-associated virus vector containing a muscle-specific promoter.

Abstract

Glycogen storage disease type II (Pompe disease) causes death in infancy from cardiorespiratory failure due to acid alpha-glucosidase (GAA; acid maltase) deficiency. An AAV2 vector pseudotyped as AAV6 (AAV2/6 vector) transiently expressed high-level human GAA in GAA-knockout (GAA-KO) mice without reducing glycogen storage; however, in immunodeficient GAA-KO/SCID mice the AAV2/6 vector expressed high-level GAA and reduced the glycogen content of the injected muscle for 24 weeks. A CD4+/CD8+ lymphocytic infiltrate was observed in response to the AAV2/6 vector in immunocompetent GAA-KO mice. When a muscle-specific creatine kinase promoter was substituted for the CB promoter (AAV-MCKhGAApA), that AAV2/6 vector expressed high-level GAA and reduced glycogen content in immunocompetent GAA-KO mice. Muscle-restricted expression of hGAA provoked only a humoral (not cellular) immune response. Intravenous administration of a high number of particles of AAV-MCKhGAApA as AAV2/7 reduced the glycogen content of the heart and skeletal muscle and corrected individual myofibers in immunocompetent GAA-KO mice 24 weeks postinjection. In summary, persistent correction of muscle glycogen content was achieved with an AAV vector containing a muscle-specific promoter in GAA-KO mice, and this approach should be considered for muscle-targeted gene therapy in Pompe disease.

• Authors: Baodong Sun, Haoyue Zhang, Luis M Franco, Talmage Brown, Andrew Bird, Ayn Schneider, Dwight D Koeberl
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 11 Issue 6 Pg. 889-98 (Jun 2005) ISSN: 1525-0016 [Print] United States
• PMID: 15922959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Antibodies (blood)
• Antibody Formation
• Creatine Kinase (genetics)
• Creatine Kinase, MM Form
• DNA, Viral (analysis)
• Dependovirus (genetics)
• Enhancer Elements, Genetic (genetics)
• Gene Transfer Techniques
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage, genetics)
• Glycogen (analysis)
• Glycogen Storage Disease Type II (genetics, therapy)
• Humans
• Injections, Intramuscular
• Isoenzymes (genetics)
• Mice
• Mice, Knockout
• Muscle, Skeletal (chemistry, enzymology)
• Myocardium (chemistry, enzymology)
• Promoter Regions, Genetic (genetics)
• alpha-Glucosidases (analysis, genetics, immunology)