Sustained hepatic and renal glucose-6-phosphatase expression corrects glycogen storage disease type Ia in mice.
Deficiency of glucose-6-phosphatase (G6Pase), a key enzyme in glucose homeostasis, causes glycogen storage disease type Ia (GSD-Ia), an autosomal recessive disorder characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. G6Pase is an endoplasmic reticulum-associated transmembrane protein expressed primarily in the liver and the kidney. Therefore, enzyme replacement therapy is not feasible using current strategies, but somatic gene therapy, targeting G6Pase to the liver and the kidney, is an attractive possibility. Previously, we reported the development of a mouse model of G6Pase deficiency that closely mimics human GSD-Ia. Using neonatal GSD-Ia mice, we now demonstrate that a combined adeno virus and adeno-associated virus vector-mediated gene transfer leads to sustained G6Pase expression in both the liver and the kidney and corrects the murine GSD-Ia disease for at least 12 months. Our results suggest that human GSD-Ia would be treatable by gene therapy.
Section on Cellular Differentiation, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Mao-Sen
MS
Sun
Chi-Jiunn
CJ
Pan
Jeng-Jer
JJ
Shieh
Abhijit
A
Ghosh
Li-Yuan
LY
Chen
Brian C
BC
Mansfield
Jerrold M
JM
Ward
Barry J
BJ
Byrne
Janice Yang
JY
Chou
D000256:Adenoviridae; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D006003:Glycogen / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice
D006003:Glycogen; D005952:Glucose-6-Phosphatase