Small interfering RNA inhibits hepatitis B virus replication in mice

Hilla Giladi, Mali Ketzinel-Gilad, Ludmila Rivkin, Yaakov Felig, Ofer Nussbaum, Eithan Galun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

295 Scopus citations

Abstract

Current therapies for chronic hepatitis B virus (HBV) infection are limited in their effect on viral gene expression and replication. Recent reports have shown that RNA interference can be induced in mammalian cells by short interfering RNA duplexes (siRNA). Here we studied the effects of an HBV-specific 21-bp siRNA targeted to the surface antigen region (HBsAg), where three major viral mRNAs overlap, on HBV gene expression and replication both in a cell culture system and in a mouse model for HBV replication. Transfection of siRNA into HepG2.2.15 cells, which constitutively produce HBV particles, caused a significant reduction in viral RNA production that was accompanied by a >80% drop in the secretion of viral HBsAg and HBeAg into the medium. The effect of RNAi was tested in vivo in a mouse model that we have developed for HBV infection, which entails hydrodynamic injection of a plasmid bearing the HBV genome into tail veins of mice. Injection of the HBV plasmid induces viral replication and generation of HBV viral particles detectable in the mouse sera. Co-injection of the HBV plasmid together with siRNA caused a significant inhibition in the level of viral transcripts, viral antigens, and viral DNA detected in the livers and sera of the treated mice relative to control animals. Results suggest that siRNA is capable of inhibiting HBV replication in vivo and thus may constitute a new therapeutic strategy for HBV infection.

Original languageAmerican English
Pages (from-to)769-776
Number of pages8
JournalMolecular Therapy
Volume8
Issue number5
DOIs
StatePublished - Nov 2003
Externally publishedYes

Bibliographical note

Funding Information:
We thank Meir Ohana, Devorah Olam, Carol Levi, and Reba Condiotti for their help in the in vivo experiments. We thank Jacob Rachmilewitz and Leslie A. Mitchell for critically reading the manuscript (Institute of Gene Therapy, Hadassah University Hospital, Jerusalem). We thank Orit Pappo for helping in the analysis of the liver pathology (Department of Pathology, Hadassah University Hospital, Jerusalem). This study was supported by the Blum Foundation and by the Israeli Ministry of Science.

Keywords

  • Animal model
  • Antiviral therapy
  • HBV
  • Hydrodynamic injection
  • RNAi

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