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

• Published in: Cell death & disease Vol. 12; no. 7; pp. 641 - 11
• Main Authors: Clark, Michelle P., Huynh, Thao, Rao, Shringar, Mackiewicz, Liana, Mason, Hugh, Romal, Shahla, Stutz, Michael D., Ahn, Sang H., Earnest, Linda, Sozzi, Vitina, Littlejohn, Margaret, Tran, Bang M., Wiedemann, Norbert, Vincan, Elizabeth, Torresi, Joseph, Netter, Hans J., Mahmoudi, Tokameh, Revill, Peter, Pellegrini, Marc, Ebert, Gregor
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-06-2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/106; 42; 42/109; 631/154/556; 64; 64/60; 692/308/2778; 692/308/575; 692/699/255/234/2513/1549; 82; 82/80; 96; 96/2; Animals; Antibodies; Antiviral Agents - pharmacology; Apoptosis; Azocines - pharmacology; Benzhydryl Compounds - pharmacology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Circular DNA; Deoxyribonucleic acid; Disease Models, Animal; DNA; Drug delivery; Genome, Viral; Genomes; Genotypes; Hep G2 Cells; Hepatitis; Hepatitis B; Hepatitis B - drug therapy; Hepatitis B - metabolism; Hepatitis B - pathology; Hepatitis B - virology; Hepatitis B virus - drug effects; Hepatitis B virus - genetics; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Hepatocytes - virology; Host-Pathogen Interactions; Humans; IAP protein; Immunology; Inhibitor of Apoptosis Proteins - antagonists & inhibitors; Inhibitor of Apoptosis Proteins - metabolism; Life Sciences; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver - virology; Liver cancer; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Targeted Therapy; Oral administration; Organoids; Thiazoles - pharmacology; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Virus Replication - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03924-0

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.