Minimal hepatic glucose-6-phosphatase-α activity required to sustain survival and prevent hepatocellular adenoma formation in murine glycogen storage disease type Ia

• Published in: Molecular genetics and metabolism reports 2015-06, Vol.3 (C), p.28-32
• Main Authors: Lee, Young Mok, Kim, Goo-Young, Pan, Chi-Jiunn, Mansfield, Brian C., Chou, Janice Y.
• Format: Article
• Language: English
• Subjects: Gene therapy; Glucose homeostasis; Glucose-6-phosphate transporter; Recombinant adeno-associated virus vector; SI:Therapy
• ISSN: 2214-4269; 2214-4269
• DOI: 10.1016/j.ymgmr.2015.03.001

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 70–90week-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 63–65weeks but mice expressing 0.5–1.3% of wild-type hepatic G6Pase-α activity (AAV-LL mice) sustain 4–6h of fast and grow normally to age 75–90weeks. 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. •Establish the minimal hepatic G6Pase-α activity restoration required to provide a blood glucose level that enables GSD-Ia mice grow to old age (75–90weeks).•Establish the minimal hepatic G6Pase-α activity restoration required that enables GSD-Ia mice grow to old age (75-90 weeks).•Define the lowest dose for G6Pase-α gene therapy that provides efficacy in mice, which informs a phase I/II clinical trial design in human GSD-Ia.