title: AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type Ia.
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.
authors: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. dwight.koeberl@duke.edu
authors: Dwight D
authors: DD
authors: Koeberl
authors: Carlos
authors: C
authors: Pinto
authors: Baodong
authors: B
authors: Sun
authors: Songtao
authors: S
authors: Li
authors: Daniel M
authors: DM
authors: Kozink
authors: Daniel K
authors: DK
authors: Benjamin
authors: Amanda K
authors: AK
authors: Demaster
authors: Meghan A
authors: MA
authors: Kruse
authors: Valerie
authors: V
authors: Vaughn
authors: Steven
authors: S
authors: Hillman
authors: Andrew
authors: A
authors: Bird
authors: Mark
authors: M
authors: Jackson
authors: Talmage
authors: T
authors: Brown
authors: Priya S
authors: PS
authors: Kishnani
authors: Yuan-Tsong
authors: YT
authors: Chen
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy; D005822:Genetic Vectors; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis / Q000235:genetics*; D005953:Glycogen Storage Disease Type I / Q000201:enzymology / Q000628:therapy*; D006801:Humans; D007003:Hypoglycemia / Q000201:enzymology / Q000628:therapy*; D008112:Liver Glycogen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D008112:Liver Glycogen; D005952:Glucose-6-Phosphatase