Gene therapeutic approaches to inhibit hepatitis B virus replication

Abstract

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.