Correction of glycogen storage disease type 1a in a mouse model by gene therapy.
Glycogen storage disease type 1a (GSD-1a), characterized by hypoglycemia, liver and kidney enlargement, growth retardation, hyperlipidemia, and hyperuricemia, is caused by a deficiency in glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis. To evaluate the feasibility of gene replacement therapy for GSD-1a, we have infused adenoviral vector containing the murine G6Pase gene (Ad-mG6Pase) into G6Pase-deficient (G6Pase(-/-)) mice that manifest symptoms characteristic of human GSD-1a. Whereas <15% of G6Pase(-/-) mice under glucose therapy survived weaning, a 100% survival rate was achieved when G6Pase(-/-) mice were infused with Ad-mG6Pase, 90% of which lived to 3 months of age. Hepatic G6Pase activity in Ad-mG6Pase-infused mice was restored to 19% of that in G6Pase(+/+) mice at 7-14 days post-infusion; the activity persisted for at least 70 days. Ad-mG6Pase infusion also greatly improved growth of G6Pase(-/-) mice and normalized plasma glucose, cholesterol, triglyceride, and uric acid profiles. Furthermore, liver and kidney enlargement was less pronounced with near-normal levels of glycogen depositions in both organs. Our data demonstrate that a single administration of a recombinant adenoviral vector can alleviate the pathological manifestations of GSD-1a in mice, suggesting that this disorder in humans can potentially be corrected by gene therapy.
Zingone
A
A
Heritable Disorders Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
Hiraiwa
H
H
Pan
C J
CJ
Lin
B
B
Chen
H
H
Ward
J M
JM
Chou
J Y
JY
D000256:Adenoviridae; D000818:Animals; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000378:metabolism
D019298:Glucose-6-Phosphate; D005952:Glucose-6-Phosphatase