@article{koeberl_pinto_sun_li_kozink_benjamin_demaster_kruse_vaughn_hillman_et al._2008, title={AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia}, volume={16}, ISSN={["1525-0016"]}, DOI={10.1038/mt.2008.15}, abstractNote={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 × 109 vp; 3 × 1011 vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 × 1013 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. 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 × 109 vp; 3 × 1011 vp/kg). When the vector was pseudotyped with AAV1, survival was prolonged only at a higher dose (3 × 1013 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.}, number={4}, journal={MOLECULAR THERAPY}, author={Koeberl, Dwight D. and Pinto, Carlos and Sun, Baodong and Li, Songtao and Kozink, Daniel M. and Benjamin, Daniel K., Jr. and Demaster, Amanda K. and Kruse, Meghan A. and Vaughn, Valerie and Hillman, Steven and et al.}, year={2008}, month={Apr}, pages={665–672} }