title: Glycogen storage disease type Ia mice with less than 2% of normal hepatic glucose-6-phosphatase-α activity restored are at risk of developing hepatic tumors.
abstract: Glycogen storage disease type Ia (GSD-Ia), characterized by impaired glucose homeostasis and chronic risk of hepatocellular adenoma (HCA) and carcinoma (HCC), is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC). We have previously shown that G6pc-/- mice receiving gene transfer mediated by rAAV-G6PC, a recombinant adeno-associated virus (rAAV) vector expressing G6Pase-α, and expressing 3-63% of normal hepatic G6Pase-α activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-α activity required to prevent tumor formation remained unknown. In this study, we constructed rAAV-co-G6PC, a rAAV vector expressing a codon-optimized (co) G6Pase-α and showed that rAAV-co-G6PC was more efficacious than rAAV-G6PC in directing hepatic G6Pase-α expression. Over an 88-week study, we showed that both rAAV-G6PC- and rAAV-co-G6PC-treated G6pc-/- mice expressing 3-33% of normal hepatic G6Pase-α activity (AAV mice) maintained glucose homeostasis, lacked HCA/HCC, and were protected against age-related obesity and insulin resistance. Of the eleven rAAV-G6PC/rAAV-co-G6PC-treated G6pc-/- mice harboring 0.9-2.4% of normal hepatic G6Pase-α activity (AAV-low mice), 3 expressing 0.9-1.3% of normal hepatic G6Pase-α activity developed HCA/HCC, while 8 did not (AAV-low-NT). Finally, we showed that the AAV-low-NT mice exhibited a phenotype indistinguishable from that of AAV mice expressing ≥3% of normal hepatic G6Pase-α activity. The results establish the threshold of hepatic G6Pase-α activity required to prevent HCA/HCC and show that GSD-Ia mice harboring <2% of normal hepatic G6Pase-α activity are at risk of tumor development.
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States.
authors.forename: Goo-Young
authors.initials: GY
authors.lastname: Kim
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States.
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States.
authors.forename: Joon Hyun
authors.initials: JH
authors.lastname: Kwon
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States.
authors.forename: Jun-Ho
authors.initials: JH
authors.lastname: Cho
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States.
authors.forename: Chi-Jiunn
authors.initials: CJ
authors.lastname: Pan
authors.affiliation: Division of Veterinary Resources, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.affiliation: Section on Cellular Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 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, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States. Electronic address: chouja@mail.nih.gov.
authors.forename: Janice Y
authors.initials: JY
authors.lastname: Chou
mesh_terms: D018248:Adenoma, Liver Cell / Q000201:enzymology / Q000517:prevention & control*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000517:prevention & control*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics* / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000150:complications / Q000201:enzymology / Q000628:therapy*; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000201:enzymology; D008113:Liver Neoplasms / Q000201:enzymology / Q000517:prevention & control*; D051379:Mice
chemical_list: D005952:Glucose-6-Phosphatase; D005947:Glucose
keywords: Gene therapy; Hepatocellular adenoma; Hepatocellular carcinoma; Recombinant adeno-associated virus vector