Gene therapy prevents hepatic tumor initiation in murine glycogen storage disease type Ia at the tumor‐developing stage

• Published in: Journal of inherited metabolic disease 2019-05, Vol.42 (3), p.459-469
• Main Authors: Cho, Jun‐Ho, Lee, Young Mok, Starost, Matthew F., Mansfield, Brian C., Chou, Janice Y.
• Format: Article
• Language: English
• Subjects: Adenoma; Animals; Autophagy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - prevention & control; Dependovirus - genetics; Disease Models, Animal; Gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Glucocorticoids; Gluconeogenesis; Glucose - metabolism; Glucose-6-Phosphatase - genetics; Glucose-6-Phosphatase - metabolism; glucose‐6‐phosphatase‐α; Glycogen; Glycogen Storage Disease Type I - complications; Glycogen Storage Disease Type I - enzymology; Glycogen Storage Disease Type I - therapy; hepatocellular adenoma/carcinoma; Homeostasis; Humans; Liver - enzymology; Liver cancer; Liver Neoplasms - enzymology; Liver Neoplasms - prevention & control; Mice; Mice, Knockout; Phagocytosis; pre‐receptor glucocorticoid signaling; Storage diseases; Tumors
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1002/jimd.12056

Hepatocellular adenoma/carcinoma (HCA/HCC) is a long‐term complication of glycogen storage disease type‐Ia (GSD‐Ia), which is caused by a deficiency in glucose‐6‐phosphatase‐α (G6Pase‐α or G6PC), a key enzyme in gluconeogenesis. Currently, there is no therapy to address HCA/HCC in GSD‐Ia. We have previously shown that a recombinant adeno‐associated virus (rAAV) vector‐mediated G6PC gene transfer to 2‐week‐old G6pc−/− mice prevents HCA development. However, it remains unclear whether G6PC gene transfer at the tumor developing stage of GSD‐Ia can prevent tumor initiation or abrogate the pre‐existing tumors. Using liver‐specific G6pc‐knockout (L‐G6pc−/−) mice that develop HCA/HCC, we now show that treating the mice at the tumor‐developing stage with rAAV‐G6PC restores hepatic G6Pase‐α expression, normalizes glucose homeostasis, and prevents de novo HCA/HCC development. The rAAV‐G6PC treatment also normalizes defective hepatic autophagy and corrects metabolic abnormalities in the nontumor liver tissues of both tumor‐free and tumor‐bearing mice. However, gene therapy cannot restore G6Pase‐α expression in the HCA/HCC lesions and fails to abrogate any pre‐existing tumors. We show that the expression of 11 β‐hydroxysteroid dehydrogenase type‐1 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‐α restoration. Collectively, our data show that rAAV‐mediated gene therapy can prevent de novo HCA/HCC development in L‐G6pc−/− mice at the tumor developing stage, but it cannot reduce any pre‐existing tumor burden.