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Review
Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent
Robert G. Gish a, b, , , Man-Fung Yuen c, Henry Lik Yuen Chan d, Bruce D. Given e, Ching-Lung Lai c, Stephen A. Locarnini f, Johnson Y.N. Lau g, Christine I. Wooddell e, Thomas Schluep e, David L. Lewis e
a Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
b Hepatitis B Foundation, Doylestown, PA, USA
c The University of Hong Kong, Hong Kong, China
d The Chinese University of Hong Kong, Hong Kong, China
e Arrowhead Research Corporation, Pasadena, CA, USA
f Victorian Infectious Diseases Reference Laboratory, Victoria, Australia
g Hong Kong Polytechnic University, Hong Kong, China
Received 14 May 2015, Revised 27 June 2015, Accepted 27 June 2015, Available online 27 June 2015
doi:10.1016/j.antiviral.2015.06.019
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Highlights
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New therapies for chronic hepatitis B are needed to achieve functional cure defined by sustained seroclearance of HBsAg.
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Current drugs such as NUCs and IFN often fail to reduce levels of viral antigens responsible for immune system exhaustion.
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RNA interference (RNAi) is a powerful, natural pathway that could be harnessed to reduce viral transcripts and antigenemia.
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Tremendous progress in conferring drug-like properties onto synthetic RNAi triggers has been made.
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RNAi-based drugs are likely to be a cornerstone of therapies with curative intent for chronic hepatitis B in the future.
Abstract
Current therapies for chronic hepatitis B virus infection (CHB) – nucleos(t)ide analogue reverse transcriptase inhibitors and interferons – result in low rates of functional cure defined as sustained off-therapy seroclearance of hepatitis B surface antigen (HBsAg). One likely reason is the inability of these therapies to consistently and substantially reduce the levels of viral antigen production. Accumulated evidence suggests that high serum levels of HBsAg result in exhaustion of the host immune system, rendering it unable to mount the effective antiviral response required for HBsAg clearance. New mechanistic approaches are required to produce high rates of HBsAg seroclearance in order to greatly reduce off-treatment disease progression. Already shown to be a clinically viable means of reducing gene expression in a number of other diseases, therapies based on RNA interference (RNAi) can directly target hepatitis B virus transcripts with high specificity, profoundly reducing the production of viral proteins. The fact that the viral RNA transcripts contain overlapping sequences means that a single RNAi trigger can result in the degradation of all viral transcripts, including all messenger RNAs and pregenomic RNA. Advances in the design of RNAi triggers have increased resistance to degradation and reduced nonspecific innate immune stimulation. Additionally, new methods to effectively deliver the trigger to liver hepatocytes, and specifically to the cytoplasmic compartment, have resulted in increased efficacy and tolerability. An RNAi-based drug currently in clinical trials is ARC-520, a dynamic polyconjugate in which the RNAi trigger is conjugated to cholesterol, which is coinjected with a hepatocyte-targeted, membrane-active peptide. Phase 2a clinical trial results indicate that ARC-520 was well tolerated and resulted in significant, dose-dependent reduction in HBsAg for up to 57 days in CHB patients. RNAi-based therapies may play an important role in future therapeutic regimes aimed at improving HBsAg seroclearance and eliminating the need for lifelong therapy. This paper forms part of a symposium in Antiviral Research on “An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.”
Keywords
RNAi; Hepatitis B virus; Antigenemia; Antiviral therapy; T-cell exhaustion
Corresponding author at: Liver Transplant Program, Stanford University Medical Center, 6022 La Jolla Mesa Drive, Stanford, CA 92037, USA.
Copyright © 2015 Published by Elsevier B.V.
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发表于 2015-7-18 09:19
