{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T22:17:08Z","timestamp":1785536228283,"version":"3.56.0"},"reference-count":25,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T00:00:00Z","timestamp":1551830400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002019","name":"Children's Fund for Glycogen Storage Disease Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002019","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hepatocellular adenoma\/carcinoma (HCA\/HCC) is a long\u2010term complication of glycogen storage disease type\u2010Ia <jats:bold>(<\/jats:bold>GSD\u2010Ia), which is caused by a deficiency in glucose\u20106\u2010phosphatase\u2010\u03b1 (G6Pase\u2010\u03b1 or G6PC), a key enzyme in gluconeogenesis. Currently, there is no therapy to address HCA\/HCC in GSD\u2010Ia. We have previously shown that a recombinant adeno\u2010associated virus (rAAV) vector\u2010mediated <jats:italic>G6PC<\/jats:italic> gene transfer to 2\u2010week\u2010old <jats:italic>G6pc<\/jats:italic>\u2212\/\u2212 mice prevents HCA development. However, it remains unclear whether <jats:italic>G6PC<\/jats:italic> gene transfer at the tumor developing stage of GSD\u2010Ia can prevent tumor initiation or abrogate the pre\u2010existing tumors. Using liver\u2010specific <jats:italic>G6pc<\/jats:italic>\u2010knockout (L<jats:italic>\u2010G6pc<\/jats:italic>\u2212\/\u2212) mice that develop HCA\/HCC, we now show that treating the mice at the tumor\u2010developing stage with rAAV\u2010G6PC restores hepatic G6Pase\u2010\u03b1 expression, normalizes glucose homeostasis, and prevents de novo HCA\/HCC development. The rAAV\u2010G6PC treatment also normalizes defective hepatic autophagy and corrects metabolic abnormalities in the nontumor liver tissues of both tumor\u2010free and tumor\u2010bearing mice. However, gene therapy cannot restore G6Pase\u2010\u03b1 expression in the HCA\/HCC lesions and fails to abrogate any pre\u2010existing tumors. We show that the expression of 11 \u03b2\u2010hydroxysteroid dehydrogenase type\u20101 that mediates local glucocorticoid activation is downregulated in HCA\/HCC lesions, leading to impairment in glucocorticoid signaling critical for gluconeogenesis activation. This suggests that local glucocorticoid action downregulation in the HCA\/HCC lesions may suppress gene therapy mediated G6Pase\u2010\u03b1 restoration. Collectively, our data show that rAAV\u2010mediated gene therapy can prevent de novo HCA\/HCC development in L<jats:italic>\u2010G6pc<\/jats:italic>\u2212\/\u2212 mice at the tumor developing stage, but it cannot reduce any pre\u2010existing tumor burden.<\/jats:p>","DOI":"10.1002\/jimd.12056","type":"journal-article","created":{"date-parts":[[2019,3,7]],"date-time":"2019-03-07T05:07:10Z","timestamp":1551935230000},"page":"459-469","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Gene therapy prevents hepatic tumor initiation in murine glycogen storage disease type Ia at the tumor\u2010developing stage"],"prefix":"10.1002","volume":"42","author":[{"given":"Jun\u2010Ho","family":"Cho","sequence":"first","affiliation":[{"name":"Section on Cellular Differentiation, Division of Translational Medicine Eunice Kennedy Shriver National Institute of Child Health and Human Development  Bethesda 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