Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Feb 27, 2015; 7(2): 150-164
Published online Feb 27, 2015. doi: 10.4254/wjh.v7.i2.150
Gene therapeutic approaches to inhibit hepatitis B virus replication
Maren Gebbing, Thorsten Bergmann, Eric Schulz, Anja Ehrhardt
Maren Gebbing, Thorsten Bergmann, Eric Schulz, Anja Ehrhardt, Institute of Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, University Witten/Herdecke, 58453 Witten, Germany
Author contributions: Gebbing M mainly contributed to this review; Bergmann T and Schulz E equally contributed to this work; Ehrhardt A contributed to and finalized this review.
Supported by The Else-Kröner-Fresenius-Foundation (EKFS) and the UWH Forschungsförderung.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Anja Ehrhardt, PhD, Institute of Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Department of Human Medicine, Faculty of Health, University Witten/Herdecke, Alfred-Herrhausen-Straße 50, 58453 Witten, Germany.
Telephone: +49-2302-926273 Fax: +49-2302-92644278
Received: August 27, 2014
Peer-review started: August 29, 2014
First decision: October 14, 2014
Revised: October 23, 2014
Accepted: November 17, 2014
Article in press: November 19, 2014
Published online: February 27, 2015

Acute and chronic hepatitis B virus (HBV) infections remain to present a major global health problem. The infection can be associated with acute symptomatic or asymptomatic hepatitis which can cause chronic inflammation of the liver and over years this can lead to cirrhosis and the development of hepatocellular carcinomas. Currently available therapeutics for chronically infected individuals aim at reducing viral replication and to slow down or stop the progression of the disease. Therefore, novel treatment options are needed to efficiently combat and eradicate this disease. Here we provide a state of the art overview of gene therapeutic approaches to inhibit HBV replication. We discuss non-viral and viral approaches which were explored to deliver therapeutic nucleic acids aiming at reducing HBV replication. Types of delivered therapeutic nucleic acids which were studied since many years include antisense oligodeoxynucleotides and antisense RNA, ribozymes and DNAzymes, RNA interference, and external guide sequences. More recently designer nucleases gained increased attention and were exploited to destroy the HBV genome. In addition we mention other strategies to reduce HBV replication based on delivery of DNA encoding dominant negative mutants and DNA vaccination. In combination with available cell culture and animal models for HBV infection, in vitro and in vivo studies can be performed to test efficacy of gene therapeutic approaches. Recent progress but also challenges will be specified and future perspectives will be discussed. This is an exciting time to explore such approaches because recent successes of gene therapeutic strategies in the clinic to treat genetic diseases raise hope to find alternative treatment options for patients chronically infected with HBV.

Keywords: Gene therapy, Hepatitis B virus, Antisense nucleic acid, RNA interference, Designer nuclease, Ribozyme, DNAzyme, Dominant negative mutant, External guide sequence, DNA vaccination

Core tip: With various successful clinical trials ongoing, gene therapeutic approaches gained increasing attention in the community over the recent years. Here we introduce gene therapy as a versatile platform for treatment of hepatitis B (HBV) virus infection. Newest delivery methods based on non-viral and viral techniques combined with most advanced technologies for inhibition of HBV replication based on DNA, RNA and designer nucleases are discussed. An overview of various gene therapeutic systems which were explored in vitro and in vivo is provided. Advantages but also limitations of the different strategies to inhibit HBV replication are mentioned.