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主要健康问题。虽然有有效的药物和疫苗的B型肝炎（HBV）感染，有近200，000，000人感染全世界。据估计，2%至4%的美国人感染丙型肝炎病毒感染（HCV），并且它是西方世界肝移植的主要指征。对于HCV感染，干扰素/Ribavarin治疗是昂贵的，困难的，并且在大多数情况下无效。新的小分子药物正在开发中，但它们靶向一种特定的蛋白质，导致感染性HCV准种的出现，从而导致对治疗药物的快速耐药性。RNA干扰（RNAi）是一种关闭细胞中基因的强大新方法，使其成为治疗感染过程的替代治疗方法。此外，可以设计策略来最小化逃逸突变体形成的可能性。我们已经初步成功地使用新的AAV载体在转基因小鼠模型中实现了HBV复制的安全和持续的>100倍减少。有趣的是，我们已经发现了一些有趣的生物反应，在体内过表达的shRNA。我们的方法是开发一种可用于治疗肝炎病毒感染的RNAi基因治疗剂。为此，我们将：（1）继续使用HBV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HCV的稳健shRNA表达序列;（3）在HCV体内复制的真正小鼠模型中测试新型AAVshRNA表达盒。我们相信，在授权期间产生的数据将开发必要的试剂，以进行HCV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.