Journal
MOLECULAR GENETICS AND METABOLISM
Volume 120, Issue 3, Pages 229-234Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2017.01.003
Keywords
Gene therapy; Recombinant adeno-associated virus vector; Hepatocellular adenoma; Hepatocellular carcinoma
Funding
- Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
- Children's Fund for Glycogen Storage Disease Research
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Glycogen storage disease type la (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-alpha (G6Pase-alpha 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-alpha, and expressing 3-63% of normal hepatic G6Pase-alpha activity maintain glucose homeostasis and do not develop HCA/HCC. However, the threshold of hepatic G6Pase-alpha 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-alpha and showed that rAAV-co-G6PC was more efficacious than rAAV-G6PC in directing hepatic G6Pase-alpha 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-alpha 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-alpha activity (AAV-low mice), 3 expressing 0.9-1.3% of normal hepatic G6Pase-alpha activity developed HCA/HCC, while 8 did not (AAV-low-NT). Finally, we showed that the MV-low-NT mice exhibited a phenotype indistinguishable from that of AAV mice expressing >= 3% of normal hepatic G6Pase-alpha activity. The results establish the threshold of hepatic G6Pase-alpha activity required to prevent HCA/HCC and show that GSD-Ia mice harboring <2% of normal hepatic G6Pase-alpha activity are at risk of tumor development. Published by Elsevier Inc.
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