Authors:
Dwight D Koeberl, Carlos Pinto, Baodong Sun, Songtao Li, Daniel M Kozink, Daniel K Benjamin Jr., Amanda K Demaster, Meghan A Kruse, Valerie Vaughn, Steven Hillman, Andrew Bird, Mark Jackson, Talmage Brown, Priya S Kishnani, and Yuan-Tsong Chen
Summary:
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.
Source:
Molecular Therapy; 16 4 665–672 (03/11/08).