A Therapeutic Silencing RNA Targeting Hepatocyte TAZ Prevents and Reverses Fibrosis in Nonalcoholic Steatohepatitis in Mice

Abstract

Nonalcoholic steatohepatitis (NASH) is emerging as a major public health issue and is associated with significant liver‐related morbidity and mortality. At present, there are no approved drug therapies for NASH. The transcriptional coactivator with PDZ‐binding motif (TAZ; encoded by WW domain‐containing transcription regulator 1 [WWTR1]) is up‐regulated in hepatocytes in NASH liver from humans and has been shown to causally promote inflammation and fibrosis in mouse models of NASH. As a preclinical test of targeting hepatocyte TAZ to treat NASH, we injected stabilized TAZ small interfering RNA (siRNA) bearing the hepatocyte‐specific ligand N‐acetylgalactosamine (GalNAc‐siTAZ) into mice with dietary‐induced NASH. As a preventative regimen, GalNAc‐siTAZ inhibited inflammation, hepatocellular injury, and the expression of profibrogenic mediators, accompanied by decreased progression from steatosis to NASH. When administered to mice with established NASH, GalNAc‐siTAZ partially reversed hepatic inflammation, injury, and fibrosis. Conclusion: Hepatocyte‐targeted siTAZ is potentially a novel and clinically feasible treatment for NASH.