RNAi for the Treatment of Viral Hepatitis

描述(由申请人提供)： 肝炎病毒感染仍然是全世界的一个主要健康问题。尽管有有效的药物和疫苗来治疗乙肝(乙肝)感染，但全球仍有近2亿人感染。据估计，美国有2%到4%的人感染了丙型肝炎病毒(HCV)，这是西方国家肝移植的主要适应症。对于丙型肝炎病毒感染，干扰素/利巴瓦林治疗昂贵、困难，而且在大多数情况下无效。新的小分子药物正在开发中，但它们针对的是一种特定的蛋白，导致出现传染性的丙型肝炎病毒准物种，导致对治疗药物的快速耐药。RNA干扰(RNAi)是关闭细胞中基因的一种强大的新方法，使其成为治疗感染过程的另一种治疗方法。此外，可以设计策略来最大限度地减少逃逸突变形成的可能性。我们已经初步成功地使用了一种新的AAV载体，在转基因小鼠模型中实现了安全和持续的&gt；100倍的乙肝复制减少。有趣的是，我们在体内发现了一些对shRNA过度表达的有趣的生物学反应。我们的方法是开发一种对治疗肝炎病毒感染有用的RNAi基因疗法。为此，我们将：(1)继续使用乙肝病毒的小鼠模型来研究体内对shRNA表达的基本生物学反应；(2)开发针对丙型肝炎病毒的强大的shRNA表达序列；以及(3)在真实的丙型肝炎病毒体内复制的小鼠模型中测试新型AAV shRNA表达盒。我们相信，在批准期间产生的数据将开发必要的试剂，以进行丙型肝炎病毒感染的I期临床试验。

DESCRIPTION (provided by applicant): Hepatitis virus infection remains a major health issue throughout the world. Although there are effective drugs and a vaccine for hepatitis B (HBV) infection, there are almost 200,000,000 people infected worldwide. It is estimated that 2 to 4% of Americans are infected with Hepatitis C Virus Infection (HCV), and it is the leading indication for liver transplantation in the western world. For HCV infection, interferon/Ribavarin therapy is expensive, difficult, and not effective in a majority of cases. New small molecule drugs are being developed, but they target a specific protein resulting in the emergence of infectious HCV quasi-species, leading to quick resistance to the therapeutic. RNA interference (RNAi) is a powerful new approach to turning off genes in cells, making it an alternative therapeutic approach to treat infectious processes. Moreover, strategies can be designed to minimize the possibility of escape mutant formation. We have had preliminary success in using a new AAV vector to achieve a safe and sustained >100 times reduction in HBV replication in a transgenic mouse model. Interestingly, we have come across some interesting biological responses to overexpression of shRNA in vivo. Our approach is to develop an RNAi gene therapeutic that would be useful for treating hepatitis virus infection. To do this we will: (1) continue to use a mouse model of HBV to study basic biological responses to shRNA expression in vivo; (2) develop robust shRNA expression sequences against HCV; and (3) test novel AAV shRNA expression cassettes in a bona-fide mouse model of HCV replication in vivo. We believe the data generated during the granting period will develop the reagents necessary to pursue a Phase I clinical trial for HCV infection.