AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia

Koeberl, D.D. et al. (2008) AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia. Molecular Therapy, 16(4), pp. 665-672. (doi: 10.1038/mt.2008.15)

Abstract

Glycogen storage disease type Ia (GSD-Ia) profoundly impairs glucose release by the liver due to glucose-6-phosphatase (G6Pase) deficiency. An adeno-associated virus (AAV) containing a small human G6Pase transgene was pseudotyped with AAV8 (AAV2/8) to optimize liver tropism. Survival was prolonged in 2-week-old G6Pase (-/-) mice by 600-fold fewer AAV2/8 vector particles (vp), in comparison to previous experiments involving this model (2 x 10(9) vp; 3 x 10(11) vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 x 10(13) vp/kg). The AAV2/8 vector uniquely prevented hypoglycemia during fasting and fully corrected liver G6Pase deficiency in GSD-Ia mice and dogs. The AAV2/8 vector has prolonged survival in three GSD-Ia dogs to >11 months, which validated this strategy in the large animal model for GSD-Ia. Urinary biomarkers, including lactate and 3-hydroxybutyrate, were corrected by G6Pase expression solely in the liver. Glycogen accumulation in the liver was reduced almost to the normal level in vector-treated GSD-Ia mice and dogs, as was the hepatocyte growth factor (HGF) in GSD-Ia mice. These preclinical data demonstrated the efficacy of correcting hepatic G6Pase deficiency, and support the further preclinical development of AAV vector-mediated gene therapy for GSD-Ia.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jackson, Dr Mark
• Authors: Koeberl, D.D., Pinto, C., Sun, B., Li, S., Kozink, D.M., Benjamin Jr., D.K., Demaster, A.K., Kruse, M.A., Vaughn, V., Hillman, S., Bird, A., Jackson, M., Brown, T., Kishnani, P.S., and Chen, Y.-T.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Molecular Therapy
• ISSN: 1525-0016