2. Academic Validation
  3. Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models

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

  • Cell Death Dis. 2021 Jun 23;12(7):641. doi: 10.1038/s41419-021-03924-0.
Michelle P Clark  # 1 2,  Thao Huynh  # 3,  Shringar Rao 4,  Liana Mackiewicz 1,  Hugh Mason 3,  Shahla Romal 4,  Michael D Stutz 1 2 5,  Sang H Ahn 6,  Linda Earnest 7,  Vitina Sozzi 3,  Margaret Littlejohn 3 8,  Bang M Tran 8,  Norbert Wiedemann 9,  Elizabeth Vincan 3 8 10,  Joseph Torresi 7,  Hans J Netter 3,  Tokameh Mahmoudi 4,  Peter Revill  # 3 7,  Marc Pellegrini  # 11 12,  Gregor Ebert  # 13 14 15
Affiliations

Affiliations

  • 1 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
  • 2 Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
  • 3 Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • 4 Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 5 Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, USA.
  • 6 Department of Internal Medicine, Yonsei University, Seoul, South Korea.
  • 7 Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • 8 Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
  • 9 Debiopharm International S.A., Lausanne, Switzerland.
  • 10 Curtin Medical School, Curtin University, Perth, WA, Australia.
  • 11 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. pellegrini@wehi.edu.au.
  • 12 Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. pellegrini@wehi.edu.au.
  • 13 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. gregor.ebert@tum.de.
  • 14 Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. gregor.ebert@tum.de.
  • 15 Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany. gregor.ebert@tum.de.
  • # Contributed equally.
PMID: 34162831 DOI: 10.1038/s41419-021-03924-0
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.

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