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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Koeberl, DD; Pinto, C; Sun, B; Li, S; Kozink, DM; Benjamin, DK; Demaster, AK; Kruse, MA; Vaughn, V; Hillman, S; Bird, A; Jackson, M; Brown, T; Kishnani, PS; Chen, Y-T

Published Date

  • April 2008

Published In

Volume / Issue

  • 16 / 4

Start / End Page

  • 665 - 672

PubMed ID

  • 18362924

Electronic International Standard Serial Number (EISSN)

  • 1525-0024

Digital Object Identifier (DOI)

  • 10.1038/mt.2008.15


  • eng

Conference Location

  • United States