Journal article

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

CELL DEATH & DISEASE | SPRINGERNATURE | Published : 2021

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..

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Grants

Awarded by Australian National Health and Medical Research Council


Awarded by Australian Center for HIV and Hepatitis Virology-ACH2


Awarded by Melbourne Health


Funding Acknowledgements

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.