AASLD 2013: ARC-520 RNAi

StephenW

TITLE: ARC-520 RNAi therapeutic reduces hepatitis B virus DNA, S antigen and e antigen in a chimpanzee with a very high viral titer
AUTHORS (FIRST NAME, LAST NAME): Robert E. Lanford1, Christine I. Wooddell2, Deborah Chavez1, Claudia Oropeza3, Qili Chu2, Holly L. Hamilton2, Alan McLachlan3, Bruce Given4, Christopher R. Anzalone4, David L. Lewis2
Institutional Author(s):
INSTITUTIONS (ALL): 1. Texas Biomedical Research Institute, San Antonio, TX, United States.
2. Arrowhead Madison, Arrowhead Research Corporation, Madison, WI, United States.
3. Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, United States.
4. Corporate Office, Arrowhead Research Corporation, Pasadena, CA, United States.
ABSTRACT BODY: Chronic hepatitis B virus (HBV) infection is a major disease world-wide for which there remains an unmet medical need. Current therapies have little effect on the viral proteins that allow sustained infection and progression of disease, and prevent the patient from mounting an effective immune response. We are developing a small interfering RNA (siRNA)-based therapeutic named ARC-520 that is designed to decrease viral protein load by the mechanism of RNA interference (RNAi). We have shown that a single intravenous injection of ARC-520 results in multi-log repression of viral RNA, proteins and DNA with long duration of effect (more than one month) in transient and transgenic mouse models of chronic HBV infection, without toxicity. Here, we present studies that demonstrate dose-dependent reduction of HBV DNA in serum and liver, HBV transcripts in liver, HBsAg, HBeAg and core antigen from single or multiple doses of ARC-520 in mice. Multiple doses of ARC-520 enabled an extended duration of effect. Recently we extended our investigations of ARC-520 to treatment of a chimpanzee chronically infected with HBV since 1979. This animal was 36-years old, weighed 51 kg and had a very high viral titer of HBV genotype B (1E+10 GE/ml serum). A single intravenous injection of 2 mg/kg of ARC-520 was well-tolerated and resulted in decreases in serum levels of HBsAg, HBeAg and HBV DNA. A subsequent injection of 3 mg/kg two weeks after the first injection correlated with increased pharmacological effect, giving 81-96% reductions in these HBV parameters at nadir. These reductions were similar in magnitude and duration of effect to those observed in the mouse HBV models receiving similar doses. The efficacy and safety of ARC-520 in a large primate demonstrate its promise as a new class of therapeutic for patients chronically infected with HBV.

StephenW

慢性B型肝炎病毒（HBV）感染是一个全球范围内的重大疾病，仍有满足医疗需求。目前的治疗方法没有什么影响病毒的蛋白质，使持续的感染和疾病的进展，防止患者安装有效的免疫反应。我们正在开发一种小分子干扰核糖核酸（RNA干扰）为基础的治疗，名为ARC -520 RNA干扰（RNAi）机制，旨在减少病毒蛋白负载。我们已经表明， ARC - 520的结果与在瞬态和慢性HBV感染的转基因小鼠模型的效果持续时间长（超过1个月） ，无毒性的病毒RNA ，蛋白质和DNA在多日志压制的单次静脉注射。在这里，我们提出了剂量依赖性降低血清和肝脏中的HBV DNA肝脏HBV成绩单，乙肝表面抗原， e抗原和核心抗原从单个或多个剂量的ARC -520在小鼠的研究表明。多个剂量的ARC - 520使能的效果的持续时间延长。最近，我们扩展我们的调查，自1979年以来，慢性HBV感染的黑猩猩的ARC -520治疗。这种动物是36岁，重达51公斤，有一个非常高的病毒滴度HBV基因型B （1E +10 GE /毫升血清） 。单次静脉注射2毫克/公斤的ARC -520的耐受性良好，导致血清中的HBsAg ， HBeAg和HBV DNA水平减少。其后，注射3毫克/公斤与增加的药理作用，在第一次注射后两周达到最低点为81-96 ％减少这些HBV参数的。这些减少接收相似剂量的小鼠HBV模型中观察到的相似的幅值和持续时间的效果。 ARC -520的疗效和安全性在一个大的灵长类动物证明其承诺作为一类新的治疗慢性HBV感染的患者。


在黑猩猩的乙肝表面抗原

咬牙硬挺

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