title: Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia.
abstract: Glycogen storage disease type Ia (GSDIa; von Gierke disease; MIM 232200) is caused by a deficiency in glucose-6-phosphatase-alpha. Patients with GSDIa are unable to maintain glucose homeostasis and suffer from severe hypoglycemia, hepatomegaly, hyperlipidemia, hyperuricemia, and lactic acidosis. The canine model of GSDIa is naturally occurring and recapitulates almost all aspects of the human form of disease. We investigated the potential of recombinant adeno-associated virus (rAAV) vector-based therapy to treat the canine model of GSDIa. After delivery of a therapeutic rAAV2/8 vector to a 1-day-old GSDIa dog, improvement was noted as early as 2 weeks posttreatment. Correction was transient, however, and by 2 months posttreatment the rAAV2/8-treated dog could no longer sustain normal blood glucose levels after 1 hr of fasting. The same animal was then dosed with a therapeutic rAAV2/1 vector delivered via the portal vein. Two months after rAAV2/1 dosing, both blood glucose and lactate levels were normal at 4 hr postfasting. With more prolonged fasting, the dog still maintained near-normal glucose concentrations, but lactate levels were elevated by 9 hr, indicating that partial correction was achieved. Dietary glucose supplementation was discontinued starting 1 month after rAAV2/1 delivery and the dog continues to thrive with minimal laboratory abnormalities at 23 months of age (18 months after rAAV2/1 treatment). These results demonstrate that delivery of rAAV vectors can mediate significant correction of the GSDIa phenotype and that gene transfer may be a promising alternative therapy for this disease and other genetic diseases of the liver.
authors.affiliation: Glycogen Storage Disease Program, Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Weinstein
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Correia
authors.forename: Thomas
authors.initials: T
authors.lastname: Conlon
authors.forename: Andrew
authors.initials: A
authors.lastname: Specht
authors.forename: John
authors.initials: J
authors.lastname: Verstegen
authors.forename: Karine
authors.initials: K
authors.lastname: Onclin-Verstegen
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: Gurmeet
authors.initials: G
authors.lastname: Dhaliwal
authors.forename: Layla
authors.initials: L
authors.lastname: Mirian
authors.forename: Holly
authors.initials: H
authors.lastname: Cossette
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Falk
authors.forename: Sean
authors.initials: S
authors.lastname: Germain
authors.forename: Nathalie
authors.initials: N
authors.lastname: Clement
authors.forename: Stacy
authors.initials: S
authors.lastname: Porvasnik
authors.forename: Laurie
authors.initials: L
authors.lastname: Fiske
authors.forename: Maggie
authors.initials: M
authors.lastname: Struck
authors.forename: Harvey E
authors.initials: HE
authors.lastname: Ramirez
authors.forename: Juan
authors.initials: J
authors.lastname: Jordan
authors.forename: Karl
authors.initials: K
authors.lastname: Andrutis
authors.forename: Janice Y
authors.initials: JY
authors.lastname: Chou
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.forename: Cathryn S
authors.initials: CS
authors.lastname: Mah
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004285:Dogs; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D005953:Glycogen Storage Disease Type I / Q000235:genetics / Q000628:therapy*; D006801:Humans