1. ¹Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA
2. ²College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA

Correspondence: Dwight D. Koeberl, DUMC Box 3528, Bell Building, Duke University Medical Center, Durham, NC 27710, USA. E-mail: koebe001@mc.duke.edu

Received 7 May 2004; Accepted 11 January 2005.

Abstract

Glycogen storage disease type II (Pompe disease) causes death in infancy from cardiorespiratory failure due to acid -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.