AAV serotype 8-mediated liver specific GNMT expression delays progression of hepatocellular carcinoma and prevents carbon tetrachloride-induced liver damage.

Abstract	Glycine N-methyltransferase (GNMT) is abundantly expressed in normal livers and plays a protective role against tumor formation. GNMT depletion leads to progression of hepatocellular carcinoma (HCC). In this study, we investigated the activity of ectopic GNMT delivered using recombinant adeno-associated virus (AAV) gene therapy in mouse models of liver cirrhosis and HCC. Injection of AAV serotype 8 (AAV8) vector carrying the GNMT gene (AAV8-GNMT) in Gnmt-/- mice increased GNMT expression and downregulated pro-inflammatory responses, resulting in reduced liver damage and incidence of liver tumors. Moreover, AAV8-GNMT resulted in the amelioration of carbon tetrachloride (CCl4)-induced liver fibrosis in BALB/c mice. We showed that AAV8-GNMT protected hepatocytes from CCl4-induced liver damage. AAV8-GNMT significantly attenuated the levels of pro-fibrotic markers and increased efficiency of hepatocyte proliferation. These results suggest that correction of hepatic GNMT by gene therapy of AAV8-mediated gene enhancement may provide a potential strategy for preventing and delaying development of liver diseases.
Authors	Cheng-Chieh Fang, Ching-Fen Wu, Yi-Jen Liao, Shiu-Feng Huang, Marcelo Chen, Yi-Ming Arthur Chen
Journal	Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 13802 (09 14 2018) ISSN: 2045-2322 [Electronic] England
PMID	30217986 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Carbon Tetrachloride GNMT protein, human Glycine N-Methyltransferase
Topics	Animals Carbon Tetrachloride (adverse effects) Carcinoma, Hepatocellular (genetics, metabolism, pathology, therapy) Cell Proliferation (physiology) Chemical and Drug Induced Liver Injury (enzymology, prevention & control) DNA Methylation Dependovirus (enzymology, genetics) Disease Progression Down-Regulation Female Genetic Therapy (methods) Glycine N-Methyltransferase (biosynthesis, genetics, metabolism) Liver Neoplasms (genetics, metabolism, pathology, therapy) Male Mice Mice, Inbred BALB C Mice, Inbred C57BL

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