Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models

Michelle P. Clark, Thao Huynh, Shringar Rao, Liana Mackiewicz, Hugh Mason, Shahla Romal, Michael D. Stutz, Sang H. Ahn, Linda Earnest, Vitina Sozzi, Margaret Littlejohn, Bang M. Tran, Norbert Wiedemann, Elizabeth Vincan, Joseph Torresi, Hans J. Netter, Tokameh Mahmoudi, Peter Revill, Marc Pellegrini, Gregor Ebert

Research output: Contribution to journalArticlepeer-review

Abstract

A major unmet clinical need is a therapeutic capable of removing hepatitis B virus (HBV) genome from the liver of infected individuals to reduce their risk of developing liver cancer. A strategy to deliver such a therapy could utilize the ability to target and promote apoptosis of infected hepatocytes. Presently there is no clinically relevant strategy that has been shown to effectively remove persistent episomal covalently closed circular HBV DNA (cccDNA) from the nucleus of hepatocytes. We used linearized single genome length HBV DNA of various genotypes to establish a cccDNA-like reservoir in immunocompetent mice and showed that clinical-stage orally administered drugs that antagonize the function of cellular inhibitor of apoptosis proteins can eliminate HBV replication and episomal HBV genome in the liver. Primary human liver organoid models were used to confirm the clinical relevance of these results. This study underscores a clinically tenable strategy for the potential elimination of chronic HBV reservoirs in patients.

Original languageEnglish
Article number641
JournalCell Death and Disease
Volume12
Issue number7
DOIs
Publication statusPublished - 2021 Jul

Bibliographical note

Funding Information:
This work was supported by Australian National Health and Medical Research Council Project Grants 1006592, 1045549, and 1065626 (MP) and APP1145977 (PR); Australian Center for HIV and Hepatitis Virology—ACH2 (LE, JT, GE, ML); Melbourne Health Grant PG-002-2016 (LV, GE), The Sylvia & Charles Viertel Senior Medical Research Fellowship (MP); Royal Melbourne Hospital Keir Fellowship (PR), the Victorian State Government Operational Infrastructure Support; the Independent Research Institutes Infrastructure Support Scheme of the Australian Government NHMRC.

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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