title: Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent.
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 57days 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."
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA; Hepatitis B Foundation, Doylestown, PA, USA. Electronic address: rgish@robertgish.com.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gish
authors.affiliation: The University of Hong Kong, Hong Kong, China.
authors.forename: Man-Fung
authors.initials: MF
authors.lastname: Yuen
authors.affiliation: The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Henry Lik Yuen
authors.initials: HL
authors.lastname: Chan
authors.affiliation: Arrowhead Research Corporation, Pasadena, CA, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Given
authors.affiliation: The University of Hong Kong, Hong Kong, China.
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Victoria, Australia.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Locarnini
authors.affiliation: Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Johnson Y N
authors.initials: JY
authors.lastname: Lau
authors.affiliation: Arrowhead Research Corporation, Pasadena, CA, USA.
authors.forename: Christine I
authors.initials: CI
authors.lastname: Wooddell
authors.affiliation: Arrowhead Research Corporation, Pasadena, CA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schluep
authors.affiliation: Arrowhead Research Corporation, Pasadena, CA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Lewis
mesh_terms: D001688:Biological Products / Q000009:adverse effects / Q000627:therapeutic use*; D001691:Biological Therapy / Q000379:methods*; D017322:Clinical Trials, Phase II as Topic; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D001688:Biological Products; D034741:RNA, Small Interfering
keywords: Antigenemia; Antiviral therapy; Hepatitis B virus; RNAi; T-cell exhaustion