Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent

作者：Robert G. Gish, Man‐Fung Yuen, Henry Lik‐Yuen Chan, Bruce D. Given, Ching‐Lung Lai, Stephen Locarnini, Johnson Y.N. Lau, Christine I. Wooddell, Thomas Schluep, David L. Lewis · 发表于：Antiviral Research · 年份：2015 · DOI：10.1016/j.antiviral.2015.06.019 · 被引用次数：130 · 研究领域：Hepatitis B Virus Studies、RNA Interference and Gene Delivery、Immunotherapy and Immune Responses

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, hav...