title: Efficacy of helper-dependent adenovirus vector-mediated gene therapy in murine glycogen storage disease type Ia.
abstract: Genetic deficiency of glucose-6-phosphatase (G6Pase) underlies glycogen storage disease type Ia (GSD-Ia, also known as von Gierke disease; MIM 232200), an autosomal recessive disorder of metabolism associated with life-threatening hypoglycemia and growth retardation. We tested whether helper-dependent adenovirus (HDAd)-mediated hepatic delivery of G6Pase would lead to prolonged survival and sustained correction of the metabolic abnormalities in G6Pase knockout (KO) mice, a model for a severe form of GSD-Ia. An HDAd vector encoding G6Pase was administered intravenously (2 or 5 x 10(12)vector particles/kg) to 2-week-old (w.o.) G6Pase-KO mice. Following HDAd vector administration survival was prolonged to a median of 7 months, in contrast to untreated affected mice that did not survive past 3 weeks of age. G6Pase levels increased more than tenfold between 3 days and 28 weeks after HDAd injection (P < 0.03). The weights of untreated 2 w.o. G6Pase-KO mice were approximately half those of their unaffected littermates, and treatment stimulated their growth to the size of wild-type mice. Severe hypoglycemia and hypercholesterolemia, which are hallmarks of GSD-Ia both in humans and in mice, were also restored to normalcy by the treatment. Glycogen accumulation in the liver was markedly reduced. The efficacy of HDAd-G6Pase treatment in reversing the physiological and biochemical abnormalities associated with GSD-Ia in affected G6Pase-KO mice justifies further preclinical evaluation in murine and canine models of GSD-Ia.
authors.affiliation: Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA. dwight.koeberl@duke.edu
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
authors.forename: B
authors.initials: B
authors.lastname: Sun
authors.forename: A
authors.initials: A
authors.lastname: Bird
authors.forename: Y T
authors.initials: YT
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Oka
authors.forename: L
authors.initials: L
authors.lastname: Chan
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D005953:Glycogen Storage Disease Type I / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
chemical_list: D006003:Glycogen; D005952:Glucose-6-Phosphatase