RNAi for the Treatment of Viral Hepatitis

RNAi 治疗病毒性肝炎

• 批准号: 8045679
• 负责人: Mark A Kay
• 金额: $ 18.32万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-12 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045679
• 关键词: Alberta province; Algorithms; American; Animal Model; Animals; Biological; Cells; Cessation of life; DNA Polymerase II; Data; Escape Mutant; Evaluation; Evolution; Exhibits; Genes; Genotype; Goals; Grant; Health; Hepatitis B; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatitis Viruses; Hepatocyte; Human; Human Viral Hepatitis; In Vitro; Individual; Infection; Infectious hepatitides; Interferons; Lead; Length; Liver; Liver Failure; Luciferases; Mediating; Monitor; Mus; Nature; Nucleotides; Pharmaceutical Preparations; Phase I Clinical Trials; Population; Positioning Attribute; Process; Proteins; RNA Interference; RNA Processing; RNA Viruses; Reagent; Relative (related person); Replication-Associated Process; Replicon; Research Personnel; Resistance; System; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Transgenic Model; Viral; Viral hepatitis; Viremia; Virus; Virus Diseases; Western World; adeno-associated viral vector; anti-hepatitis C; design; fusion gene; in vivo; interest; liver transplantation; mouse model; novel; novel strategies; overexpression; preclinical study; programs; promoter; response; small hairpin RNA; small molecule; success; therapeutic gene; vector

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.

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。尽管有针对乙型肝炎 (HBV) 感染的有效药物和疫苗，但全球仍有近 2 亿人感染。据估计，2％至4％的美国人感染丙型肝炎病毒感染（HCV），这是西方世界肝移植的主要适应症。对于 HCV 感染，干扰素/利巴韦林治疗昂贵、困难，并且在大多数情况下无效。新的小分子药物正在开发中，但它们针对特定蛋白质，导致传染性丙型肝炎病毒准种的出现，从而导致对治疗方法的快速耐药。 RNA 干扰 (RNAi) 是一种关闭细胞基因的强大新方法，使其成为治疗感染过程的替代治疗方法。此外，可以设计策略来最大程度地减少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安全、持续地将 HBV 复制减少了 100 倍以上。有趣的是，我们发现了体内 shRNA 过度表达的一些有趣的生物学反应。我们的方法是开发一种可用于治疗肝炎病毒感染的 RNAi 基因疗法。为此，我们将：（1）继续使用HBV小鼠模型来研究体内shRNA表达的基本生物学反应； (2) 开发针对 HCV 的强 shRNA 表达序列； (3) 在 HCV 体内复制的真实小鼠模型中测试新型 AAV shRNA 表达盒。我们相信，在授权期间产生的数据将开发出进行 HCV 感染 I 期临床试验所需的试剂。