Editorial
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2015; 21(23): 7084-7088
Published online Jun 21, 2015. doi: 10.3748/wjg.v21.i23.7084
Novel therapeutic approaches for hepatitis B virus covalently closed circular DNA
Motoko Ohno, Motoyuki Otsuka, Takahiro Kishikawa, Takeshi Yoshikawa, Akemi Takata, Kazuhiko Koike
Motoko Ohno, Motoyuki Otsuka, Takahiro Kishikawa, Takeshi Yoshikawa, Akemi Takata, Kazuhiko Koike, Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-8655, Japan
Author contributions: Ohno M, Otsuka M, Kishikawa T and Koike K wrote the manuscript; Yoshikawa T and Takata A prepared the figures.
Conflict-of-interest: No potential conflicts of interest relevant to this article were reported.
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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Motoyuki Otsuka, MD, Department of Gastroenterology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. otsukamo-tky@umin.ac.jp
Telephone: +81-3-58008812 Fax: +81-3-38140021
Received: January 28, 2015
Peer-review started: January 29, 2015
First decision: March 26, 2015
Revised: April 9, 2015
Accepted: May 4, 2015
Article in press: May 4, 2015
Published online: June 21, 2015
Abstract

Hepatitis B virus (HBV) infection is a major global health problem. Although current therapies, such as the use of nucleos(t)ide analogs, inhibit HBV replication efficiently, they do not eliminate covalently closed circular DNA (cccDNA), which persists in hepatocyte nuclei. As HBV cccDNA is a viral transcription template, novel therapeutic approaches to directly target HBV cccDNA are necessary to completely eradicate persistent HBV infections. HBV cccDNA levels in HBV-infected human liver cells are extremely low; thus, more reliable and simple measurement methods are needed to correctly monitor their levels during therapeutic treatment. Although reverse transcription-polymerase chain reaction or Southern blot procedures are currently used in research studies, these methods are not completely reliable and are also time-consuming and labor-intensive. Genome editing technologies, such as zinc finger nucleases, transcription activator-like effector nucleases, and the clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) system, which are designed to target specific DNA sequences, represent highly promising potential therapeutic tools. In particular, the CRISPR/Cas9 system is an easily customizable sequence-specific nuclease with high flexibility and may be the most feasible approach to target HBV cccDNA. Further research to develop easier, safer, and more effective protocols should be pursued.

Keywords: Hepatitis B virus, Covalently closed circular HBV DNA, Genome editing

Core tip: Hepatitis B virus (HBV) infection is a global health problem. Because current therapeutic approaches do not eliminate HBV nuclear covalently closed circular DNA (cccDNA), novel therapeutics to target cccDNA are needed to eradicate HBV infection. Genome editing technologies are expected to be promising therapeutic options against HBV cccDNA. In particular, the clustered regularly interspaced short palindromic repeats/Cas9 system is an easily customizable sequence-specific nuclease with great flexibility and may be the most feasible approach to target HBV cccDNA, as further research studies develop more effective protocols.