title: Minimal hepatic glucose-6-phosphatase-α activity required to sustain survival and prevent hepatocellular adenoma formation in murine glycogen storage disease type Ia.
abstract: Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC) activity. In a previous 70-90 week-study, we showed that a recombinant adeno-associated virus (rAAV) vector-mediated gene transfer that restores more than 3% of wild-type hepatic G6Pase-α activity in G6pc (-/-) mice corrects hepatic G6Pase-α deficiency with no evidence of HCA. We now examine the minimal hepatic G6Pase-α activity required to confer therapeutic efficacy. We show that rAAV-treated G6pc (-/-) mice expressing 0.2% of wild-type hepatic G6Pase-α activity suffered from frequent hypoglycemic seizures at age 63-65 weeks but mice expressing 0.5-1.3% of wild-type hepatic G6Pase-α activity (AAV-LL mice) sustain 4-6 h of fast and grow normally to age 75-90 weeks. Despite marked increases in hepatic glycogen accumulation, the AAV-LL mice display no evidence of hepatic abnormalities, hepatic steatosis, or HCA. Interprandial glucose homeostasis is maintained by the G6Pase-α/glucose-6-phosphate transporter (G6PT) complex, and G6PT-mediated microsomal G6P uptake is the rate-limiting step in endogenous glucose production. We show that hepatic G6PT activity is increased in AAV-LL mice. These findings are encouraging for clinical studies of G6Pase-α gene-based therapy for GSD-Ia.
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Goo-Young
authors.initials: GY
authors.lastname: Kim
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Chi-Jiunn
authors.initials: CJ
authors.lastname: Pan
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States; Foundation Fighting Blindness, Columbia, MD 21046, United States.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Mansfield
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Janice Y
authors.initials: JY
authors.lastname: Chou
keywords: AAV, adeno-associated virus; BW, body weight; ER, endoplasmic reticulum; G6P, glucose-6-phosphate; G6PC, glucose-6-phosphatase-α gene; G6PT, glucose-6-phosphate transporter; G6Pase-α, glucose-6-phosphatase-α; GPE, G6PC promoter and enhancer; GSD-Ia, glycogen storage disease type Ia; Gene therapy; Glucose homeostasis; Glucose-6-phosphate transporter; HCA, hepatocellular adenoma; Recombinant adeno-associated virus vector