DDW 2013: ARC520

StephenW

Long Duration of Effect From RNAI Therapeutic to Treat Chronic Hepatitis B Virus Infection Correlates With Persistence of the Phosphorylated Guide Strand

Christine I. Wooddell1, Vladimir Trubetskoy1, Collin Hagen1, Anthony Perillo-Nicholas1, Jacob B. Griffin1, Holly Hamilton1, Qili Chu1, Alan McLachlan2, David Rozema1, David Lewis1

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1Arrowhead Madison, Arrowhead Research Corporation, Madison, WI; 2Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL

Abstract:

Chronic hepatitis B virus (HBV) infection is a major disease for which there remains an unmet medical need. Current therapies for chronic hepatitis B include reverse transcriptase inhibitors and interferon. These therapies either require life-long administration or have significant side effects and limited efficacy. We have taken a novel approach toward the treatment of chronic hepatitis B by developing an siRNA-based therapeutic. In contrast to current therapies, our approach has the promise of significantly decreasing viral protein load which is primarily responsible for disease progression. In our formulation, liver-tropic cholesterol-conjugated siRNAs against HBV (chol-siHBVs) are co-injected intravenously with a reversibly masked, hepatocyte-targeted melittin-like peptide (NAG-MLP). Co-injection of chol-siHBVs and NAG-MLP results in multi-log repression of viral RNA, proteins and viral DNA with long duration of effect in transient and transgenic mouse models of chronic HBV infection, without toxicity. Using a hybridization/HPLC-based method of detection, we are able to correlate the degree of repression of the virus with the amount of the active form of the siRNA guide strand in the liver. In addition, this form of the guide strand can be detected up to one month after a single administration, correlating with the duration of effect. High efficacy, a long duration of effect and establishment of a robust pharmacokinetic/pharmacodynamic relationship in the liver suggest co-injection of NAG-MLP and chol-siHBVs holds great promise as a novel therapeutic for chronically HBV infected patients.

StephenW

与持久性磷酸指南东街起RNAi治疗治疗慢性乙型肝炎病毒感染的持续时间长
科林Hagen1弗拉基米尔Trubetskoy1，恭一Wooddell1，安东尼佩里洛Nicholas1的，雅B. Griffin1，冬青Hamilton1，七里初1，阿伦McLachlan2，大卫，大卫Rozema1 Lewis1


箭头研究公司，麦迪逊，威斯康星州;麦迪逊1Arrowhead，2Microbiology和免疫学，伊利诺伊大学芝加哥分校，芝加哥，IL

摘要：

慢性B型肝炎病毒（HBV）感染是一个主要的疾病仍有满足医疗需求。目前的治疗方法包括逆转录酶抑制剂和干扰素治疗慢性乙型肝炎。这些疗法需要终生管理，或有显着的副作用，疗效有限。我们已经采取了一种新的方法，发展的siRNA为基础的治疗，对治疗慢性乙型肝炎。目前的治疗方法相比，我们的方法具有显着降低病毒蛋白的负载，这是疾病进展的主要负责的承诺。在我们的配方，嗜肝胆固醇的共轭的siRNAs抗HBV（CHOL siHBVs）的联合静脉注射可逆蒙面，肝细胞有针对性的类似蜂毒肽（NAG-MLP）。注射哲-siHBVs和NAG-MLP结果的多日志镇压的瞬态和慢性HBV感染的转基因小鼠模型的效果持续时间长，无毒性的病毒RNA，蛋白质和病毒DNA。用一种杂交/基于HPLC的检测方法，我们能够关联程度的压制病毒与在肝脏导的siRNA链的活性形式的量。此外，这种形式的导向链可以被检测到在单次给药，以1个月后，相关的效果的持续时间。疗效高，持续时间长的影响和建立一个强大的药动学/药效学的关系在肝脏提示，NAG的-MLP和哲siHBVs的注射合作拥有巨大潜力，作为一种新的治疗慢性HBV感染的患者。