Zhu Qing, Oei Yoko, Mendel Dirk B, Garrett Evelyn N, Patawaran Montesa B, Hollenbach Paul W, Aukerman Sharon L, Weiner Amy J
Department of Pharmacology, Novartis Vaccines and Diagnostics, Chiron Corportion, Emeryville, CA 94608.
Antimicrob Agents Chemother. 2006 Oct;50(10):3260-8. doi: 10.1128/AAC.00413-06.
The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-alpha) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-alpha combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts.
丙型肝炎病毒（HCV）缺乏一种完善的小动物模型，这阻碍了针对HCV感染的新型药物治疗方法的发现和开发。我们开发了一种可重复且易于使用的异种移植小鼠疗效模型，在该模型中，通过对植入了携带小鼠适应性荧光素酶复制子的Huh-7细胞系（T7-11）的经γ射线照射的SCID小鼠进行实时、非侵入性全身成像，可在体内准确监测HCV RNA复制。通过证明小分子NS3/4A蛋白酶抑制剂（BILN 2061）和人α干扰素（IFN-α）均可降低HCV RNA复制，且停药后复制会反弹，这与人类的临床结果相似，从而验证了该模型。我们进一步表明，蛋白酶抑制剂和IFN-α联合治疗在降低HCV RNA复制方面比单独使用每种化合物更有效，并支持在人体中进行试验。这种完善的小鼠疗效模型为在体内快速评估潜在的抗HCV化合物提供了一个强大的工具，作为积极的药物发现工作的一部分。
