Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia.
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.
Weinstein
David A
DA
Glycogen Storage Disease Program, Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.
Correia
Catherine E
CE
Conlon
Thomas
T
Specht
Andrew
A
Verstegen
John
J
Onclin-Verstegen
Karine
K
Campbell-Thompson
Martha
M
Dhaliwal
Gurmeet
G
Mirian
Layla
L
Cossette
Holly
H
Falk
Darin J
DJ
Germain
Sean
S
Clement
Nathalie
N
Porvasnik
Stacy
S
Fiske
Laurie
L
Struck
Maggie
M
Ramirez
Harvey E
HE
Jordan
Juan
J
Andrutis
Karl
K
Chou
Janice Y
JY
Byrne
Barry J
BJ
Mah
Cathryn S
CS
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