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.

Details

Title
Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models
Author
Clark, Michelle P 1   VIAFID ORCID Logo  ; Huynh Thao 2   VIAFID ORCID Logo  ; Rao Shringar 3 ; Mackiewicz Liana 4 ; Mason, Hugh 2 ; Romal Shahla 3 ; Stutz, Michael D 5 ; Ahn, Sang H 6 ; Earnest, Linda 7 ; Sozzi Vitina 2 ; Littlejohn, Margaret 8   VIAFID ORCID Logo  ; Tran, Bang M 9   VIAFID ORCID Logo  ; Wiedemann Norbert 10 ; Vincan, Elizabeth 11 ; Torresi, Joseph 7 ; Netter, Hans J 2 ; Mahmoudi Tokameh 3 ; Revill, Peter 12 ; Pellegrini, Marc 1 ; Ebert, Gregor 13   VIAFID ORCID Logo 

1  The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia (GRID:grid.1042.7); The University of Melbourne, Department of Medical Biology, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
2  The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia (GRID:grid.416153.4) (ISNI:0000 0004 0624 1200) 
3  Erasmus University Medical Center, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
4  The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia (GRID:grid.1042.7) 
5  The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia (GRID:grid.1042.7); The University of Melbourne, Department of Medical Biology, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Oregon Health and Science University, Vaccine and Gene Therapy Institute, Beaverton, USA (GRID:grid.5288.7) (ISNI:0000 0000 9758 5690) 
6  Yonsei University, Department of Internal Medicine, Seoul, South Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
7  The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
8  The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia (GRID:grid.416153.4) (ISNI:0000 0004 0624 1200); The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Department of Infectious Diseases, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
9  The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Department of Infectious Diseases, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
10  Debiopharm International S.A., Lausanne, Switzerland (GRID:grid.476201.6) (ISNI:0000 0004 0627 5347) 
11  The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia (GRID:grid.416153.4) (ISNI:0000 0004 0624 1200); The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Department of Infectious Diseases, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Curtin University, Curtin Medical School, Perth, Australia (GRID:grid.1032.0) (ISNI:0000 0004 0375 4078) 
12  The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia (GRID:grid.416153.4) (ISNI:0000 0004 0624 1200); The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
13  The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia (GRID:grid.1042.7); The University of Melbourne, Department of Medical Biology, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Technical University of Munich/Helmholtz Zentrum München, Institute of Virology, Munich, Germany (GRID:grid.6936.a) (ISNI:0000000123222966) 
Publication year
2021
Publication date
Jul 2021
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41419-021-03924-0
ProQuest document ID
2544321462
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.