AAV vector-mediated reversal of hypoglycemia in canine and murine glycogen storage disease type 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 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.
Koeberl
Dwight D
DD
Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. dwight.koeberl@duke.edu
Pinto
Carlos
C
Sun
Baodong
B
Li
Songtao
S
Kozink
Daniel M
DM
Benjamin
Daniel K
DK
Demaster
Amanda K
AK
Kruse
Meghan A
MA
Vaughn
Valerie
V
Hillman
Steven
S
Bird
Andrew
A
Jackson
Mark
M
Brown
Talmage
T
Kishnani
Priya S
PS
Chen
Yuan-Tsong
YT
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
D008112:Liver Glycogen; D005952:Glucose-6-Phosphatase