Abstract
Chronic infection with the hepatitis B virus (HBV) is a global health concern and accounts for approximately 1 million deaths annually. Amongst other limitations of current anti-HBV treatment, failure to eliminate the viral covalently closed circular DNA (cccDNA) and emergence of resistance remain the most worrisome. Viral rebound from latent episomal cccDNA reservoirs occurs following cessation of therapy, patient non-compliance, or the development of escape mutants. Simultaneous viral co-infections, such as by HIV-1, further complicate therapeutic interventions. These challenges have prompted development of novel targeted hepatitis B therapies. Given the ease with which highly specific and potent nucleic acid therapeutics can be rationally designed, gene therapy has generated interest for antiviral application. Gene therapy strategies developed for HBV include gene silencing by harnessing RNA interference, transcriptional inhibition through epigenetic modification of target DNA, genome editing by designer nucleases, and immune modulation with cytokines. DNA-binding domains and effectors based on the zinc finger (ZF), transcription activator-like effector (TALE), and clustered regularly interspaced short palindromic repeat (CRISPR) systems are remarkably well suited to targeting episomal cccDNA. This review discusses recent developments and challenges facing the field of anti-HBV gene therapy, its potential curative significance and the progress towards clinical application.
Highlights
Viral hepatitis accounts for up to 1.34 million deaths per year and remains the major cause of morbidity and mortality from cirrhosis and hepatocellular carcinoma [1]
More than 50 years have passed since the discovery of the Australia antigen [2], and while valuable progress has been made in vaccine and antiviral development, there is still no reliable cure for Hepatitis B virus (HBV) infection
Worldwide prophylactic vaccination programs have reduced the prevalence of HBV in children under the age of five, but inadequate coverage in hyper-endemic African countries means that prevalence remains high in some countries [1]
Summary
Viral hepatitis accounts for up to 1.34 million deaths per year and remains the major cause of morbidity and mortality from cirrhosis and hepatocellular carcinoma [1]. Management of chronic HBV infection involves use of immune modulators or direct-acting antivirals, in the form of interferons or nucleoside/nucleotide analogs (NAs). While NAs inhibit posttranscriptional stages of viral replication, they do not target the stable episomal covalently closed circular DNA (cccDNA). This key HBV replication intermediate forms a minichromosome in the nucleus of hepatocytes [8,9,10], and may undergo epigenetic modifications [11,12,13]. This review focuses on recent advances aimed at generating HBV-targeting designer nucleases, epigenetic modifications to the viral DNA and nucleic acid-based immune modulation to treat chronic
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