乙型肝炎病毒治疗剂ARB-1740在新的双重感染的人源化小鼠模型

StephenW

ACS Infect Dis. 2018 Nov 8. doi: 10.1021/acsinfecdis.8b00192. [Epub ahead of print]
Hepatitis B Virus Therapeutic Agent ARB-1740 Has Inhibitory Effect on Hepatitis Delta Virus in a New Dually-Infected Humanized Mouse Model.
Ye X, Tateno C, Thi EP, Kakuni M, Snead NM, Ishida Y, Barnard TR, Sofia M, Shimada T, Lee ACH.
Abstract

Hepatitis delta virus (HDV) infects 10-20 million individuals worldwide and causes severe fulminant hepatitis with high likelihood of cirrhosis and hepatocellular carcinoma. HDV infection cannot occur in the absence of the surface antigen (HBsAg) of the hepatitis B virus. RNA interference is an effective mechanism by which to inhibit viral transcripts and siRNA therapeutics sharing this mechanism have begun to demonstrate clinical efficacy. Here we assessed the outcome of HBV-targeting siRNA intervention against HDV and compared it to a direct anti-HDV siRNA approach in dually-infected humanized mice. Treatment with ARB-1740, a clinical stage HBV-targeting siRNA agent delivered using lipid nanoparticle (LNP) technology, effectively reduced HBV viremia by 2.3 log10 and serum HBsAg by 2.6 log10, leading to 1.6 log10 reduction of HDV viremia. In contrast, HDV-targeting siRNA inhibited HDV in both blood and liver compartments without affecting HBV and pegylated interferon-alpha reduced HBV viremia by 2.0 log10 but had no effect on HDV viremia under these study conditions. These results illustrate the inhibitory effects of siRNAs against these two viral infections and suggest that ARB-1740 may be of therapeutic benefit for hepatitis delta patients, a subpopulation with high unmet medical need.

PMID:
    30408957
DOI:
    10.1021/acsinfecdis.8b00192

StephenW

ACS Infect Dis。 2018年11月8日doi：10.1021 / acsinfecdis.8b00192。 [提前打印]
乙型肝炎病毒治疗剂ARB-1740在新的双重感染的人源化小鼠模型中对乙型肝炎病毒具有抑制作用。
Ye X，Tateno C，Thi EP，Kakuni M，Snead NM，Ishida Y，Barnard TR，Sofia M，Shimada T，Lee ACH。
抽象

肝炎病毒（HDV）感染全世界1000万至2000万人并导致严重的暴发性肝炎，肝硬化和肝细胞癌的可能性很高。在没有乙型肝炎病毒的表面抗原（HBsAg）的情况下不能发生HDV感染。 RNA干扰是抑制病毒转录物的有效机制，共享该机制的siRNA治疗剂已开始证明临床疗效。在这里，我们评估了针对HDV的HBV靶向siRNA干预的结果，并将其与双重感染的人源化小鼠中的直接抗HDV siRNA方法进行了比较。使用脂质纳米颗粒（LNP）技术递送的临床阶段HBV靶向siRNA试剂ARB-1740治疗有效地将HBV病毒血症减少2.3log10，血清HBsAg减少2.6log10，导致HDV病毒血症减少1.6log10。相反，HDV靶向siRNA在血液和肝脏区室中抑制HDV而不影响HBV和聚乙二醇化干扰素-α使HBV病毒血症减少2.0log10，但在这些研究条件下对HDV病毒血症没有影响。这些结果说明了siRNA对这两种病毒感染的抑制作用，并表明ARB-1740可能对肝炎三角洲患者具有治疗益处，这是一种具有高度未满足医疗需求的亚群。

结论：
    30408957
DOI：
    10.1021 / acsinfecdis.8b00192