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

doi:10.1038/s41419-021-03924-0

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^*

^*Corresponding author for this work

Biochemistry

Research output: Contribution to journal › Article › Academic › peer-review

6 Citations (Scopus)

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 language	English
Article number	641
Journal	Cell Death and Disease
Volume	12
Issue number	7
DOIs	https://doi.org/10.1038/s41419-021-03924-0
Publication status	Published - 23 Jun 2021

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).

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Clark, M. P., Huynh, T., Rao, S., Mackiewicz, L., Mason, H., Romal, S., Stutz, M. D., Ahn, S. H., Earnest, L., Sozzi, V., Littlejohn, M., Tran, B. M., Wiedemann, N., Vincan, E., Torresi, J., Netter, H. J., Mahmoudi, T., Revill, P., Pellegrini, M., & Ebert, G. (2021). Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models. Cell Death and Disease, 12(7), Article 641. https://doi.org/10.1038/s41419-021-03924-0

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

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.",

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

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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jun,

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doi = "10.1038/s41419-021-03924-0",

language = "English",

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Clark, MP, Huynh, T, Rao, S, Mackiewicz, L, Mason, H, Romal, S, Stutz, MD, Ahn, SH, Earnest, L, Sozzi, V, Littlejohn, M, Tran, BM, Wiedemann, N, Vincan, E, Torresi, J, Netter, HJ, Mahmoudi, T, Revill, P, Pellegrini, M & Ebert, G 2021, 'Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models', Cell Death and Disease, vol. 12, no. 7, 641. https://doi.org/10.1038/s41419-021-03924-0

TY - JOUR

T1 - Clinical stage drugs targeting inhibitor of apoptosis proteins purge episomal Hepatitis B viral genome in preclinical models

AU - Clark, Michelle P.

AU - Huynh, Thao

AU - Rao, Shringar

AU - Mackiewicz, Liana

AU - Mason, Hugh

AU - Romal, Shahla

AU - Stutz, Michael D.

AU - Ahn, Sang H.

AU - Earnest, Linda

AU - Sozzi, Vitina

AU - Littlejohn, Margaret

AU - Tran, Bang M.

AU - Wiedemann, Norbert

AU - Vincan, Elizabeth

AU - Torresi, Joseph

AU - Netter, Hans J.

AU - Mahmoudi, Tokameh

AU - Revill, Peter

AU - Pellegrini, Marc

AU - Ebert, Gregor

N1 - 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).

PY - 2021/6/23

Y1 - 2021/6/23

N2 - 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.

AB - 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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U2 - 10.1038/s41419-021-03924-0

DO - 10.1038/s41419-021-03924-0

M3 - Article

C2 - 34162831

AN - SCOPUS:85108797380

SN - 2041-4889

VL - 12

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 7

M1 - 641

ER -

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

Abstract

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