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

Wang, Xiaobo, Sommerfeld, Mark R., Jahn‐Hofmann, Kerstin, Cai, Bishuang, Filliol, Aveline, Remotti, Helen E., Schwabe, Robert F., Kannt, Aimo, Tabas, Ira·2019·Hepatology Communications
DOI 10.1002/hep4.1405
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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.

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  • Treatment of MASH mice with GalNAc-siTaz prevents fibrosis and inflammation in MASH.

    “we have recently used siRNA conjugated to N-acetylgalactosamine (GalNAc),96 the first FDA-approved hepatocyte-target siRNA,97 to silence hepatocyte TAZ, and found that treatment of MASH mice with GalNAc-siTaz prevents fibrosis and inflammation in MASH.98,99”

    From EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis (2025) · cites this paper as [98]

  • The retromer stabilization approach may be more potent than targeting TAZ, as TAZ silencing does not alleviate steatosis.

    “This retromer stabilization approach may be more potent than targeting TAZ, as TAZ silencing does not alleviate steatosis.98,99”

    From EHBP1 suppresses liver fibrosis in metabolic dysfunction-associated steatohepatitis (2025) · cites this paper as [98]

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Research works printed but not linked: 37

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Metadata

Authors
Wang, X., Sommerfeld, M. R., Jahn‐Hofmann, K., Cai, B., Filliol, A., Remotti, H. E., Schwabe, R. F., Kannt, A., & Tabas, I.
Affiliations
  • Department of Medicine,Columbia University Irving Medical Center,New York,NY
  • Sanofi‐Aventis Deutschland GmbH,Frankfurt am Main,Germany
  • Department of Pathology and Cell Biology,Columbia University Irving Medical Center,New York,NY
ORCID
Tabas, Ira
Venue
Hepatology Communications
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-07-23
Volume
3
Issue
9
Pages
1221-1234
ISSN
2471-254X
DOI
10.1002/hep4.1405
Cited by
56
References
6
Language
en
Licence
creativecommons.org/licenses/by-nc-nd/4.0/ (unspecified)

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