In vivo reduction of hepatitis B virus antigenemia and viremia by antisense oligonucleotides

Gaetan Billioud, Robert L. Kruse, Melissa Carrillo, Christina Whitten-Bauer, Dacao Gao, Aneeza Kim, Leon Chen, Michael L. McCaleb, Jeffrey R. Crosby, Robert Hamatake, Zhi Hong, Urtzi Garaigorta, Eric Swayze, Karl Dimiter Bissig, Stefan Wieland

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Background & Aims Current treatment of chronic hepatitis B virus infection (CHB) includes interferon and nucleos(t)ide analogues, which generally do not reduce HBV surface antigen (HBsAg) production, a constellation that is associated with poor prognosis of CHB. Here we evaluated the efficacy of an antisense approach using antisense oligonucleotide (ASO) technology already in clinical use for liver targeted therapy to specifically inhibit HBsAg production and viremia in a preclinical setting. Methods A lead ASO was identified and characterized in vitro and subsequently tested for efficacy in vivo and in vitro using HBV transgenic and hydrodynamic transfection mouse and a cell culture HBV infection model, respectively. Results ASO treatment decreased serum HBsAg levels ≥2 logs in a dose and time-dependent manner; HBsAg decreased 2 logs in a week and returned to baseline 4 weeks after a single ASO injection. ASO treatment effectively reduced HBsAg in combination with entecavir, while the nucleoside analogue alone did not. ASO treatment has pan-genotypic antiviral activity in the hydrodynamic transfection system. Finally, cccDNA-driven HBV gene expression is ASO sensitive in HBV infected cells in vitro. Conclusion Our results demonstrate in a preclinical setting the efficacy of an antisense approach against HBV by efficiently reducing serum HBsAg (as well as viremia) across different genotypes alone or in combination with standard nucleoside therapy. Since the applied antisense technology is already in clinical use, a lead compound can be rapidly validated in a clinical setting and thus, constitutes a novel therapeutic approach targeting chronic HBV infection.

Original languageEnglish (US)
Pages (from-to)781-789
Number of pages9
JournalJournal of hepatology
Volume64
Issue number4
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Keywords

  • 2′MOE antisense molecule
  • HBV Infection
  • HBV transgenic mice
  • Hydrodynamic transfection

ASJC Scopus subject areas

  • Hepatology

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