Abstract
Chronic infection with hepatitis B virus (HBV) occurs in approximately 6% of the world's population and carriers of the virus are at risk for hepatocellular carcinoma and cirrhosis. Current treatment regimens, which include interferon-α and nucleoside/nucleotide analogs, are only partially effective and new treatment methods remain an important objective. Harnessing the RNA interference (RNAi) pathway to achieve post-transcriptional silencing of rogue genetic elements is an exciting avenue for development of novel therapeutic strategies. The specific and potent suppression of HBV gene expression and replication is an attractive option as a novel and effective approach for the treatment of chronic HBV infection. However, despite significant and rapid progress, existing RNAi technologies require further refinement before clinical applications can be realized. Here, we review current efforts aimed at improving the efficiency of anti-HBV RNAi-based delivery systems, at limiting the toxicities associated with RNAi modalities and at preventing reactivation of viral replication. We discuss the progress towards clinical implementation of anti-HBV RNAi therapies.
Highlights
Chronic hepatitis B virus (HBV) infection is an epidemic with approximately 387 million chronically infected carriers worldwide, and chronic infection carries a high risk for serious complications, such as cirrhosis and hepatocellular carcinoma [1,2]
RNA interference (RNAi) has an important role in regulating gene expression through the processing of long double stranded RNA (dsRNA) precursors by the RNase III enzymes Drosha and Dicer into endogenous microRNAs or short interfering RNAs
Conclusions and prospects for clinical application The progress made in the field of RNAi-based HBV therapy has been impressive
Summary
Chronic hepatitis B virus (HBV) infection is an epidemic with approximately 387 million chronically infected carriers worldwide, and chronic infection carries a high risk for serious complications, such as cirrhosis and hepatocellular carcinoma [1,2]. Weak interstrand bonding at the 5’ end of the intended guide [32] and incorporating a 5’-O-methyl group on the terminal ribose of the sense strand [33] facilitate appropriate selection of guide strands by RISC These results show that chemical modifica tions are very useful to improve the safety profile and specificity of siRNAs, which are critical for development of anti-HBV RNAi-based therapy. Abbreviations AAV, adeno-associated virus; cccDNA, covalently closed circular DNA; dsRNA, double stranded RNA; esiRNA, endoribonuclease-prepared siRNA; HBV, hepatitis B virus; IFN-α, interferon-α; miRNA, microRNA; PEG, polyethylene glycol; rcDNA, relaxed circular DNA; pDNA, plasmid DNA; RISC, RNA-induced silencing complex; RNAi, RNA interference; shRNA, short hairpin RNA; siRNA, short interfering RNA; SNALP, stable nucleic acid-lipid particle.
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