An RNAi Trojan Horse for treatment of hepatitis C.

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染全球超过1.7亿人，是需要肝移植的主要疾病。没有疫苗，目前的治疗方法往往无效，并有严重的副作用。目前有相当大的兴趣使用RNA干扰作为一种抗病毒的方式。尽管siRNAs和shRNA都可以非常有效，IC50在亚纳摩尔范围内，但将有效剂量的RNA药物输送到肝脏感染的肝细胞的能力限制了疗效。因此，在传递技术没有突破的情况下，如果要在临床上使用，就需要具有更高效力的si/shRNA。此外，尽管通过静脉途径给药到肝脏比许多其他组织更容易，但每种给药方式都允许其他器官摄取一些药物，从而在未感染的组织中产生潜在的不良影响。在这里，我们提出了一种新的方法，其中有限的细胞内递送是通过从每个治疗分子产生许多shRNA的机制来补偿的。此外，shRNAs的产生只发生在感染了丙型肝炎病毒的细胞中。因此，治疗分子可以被设计成针对病毒或宿主基因，导致病毒生长抑制或感染细胞死亡(或在联合治疗中两者兼而有之)。当药物被未感染的细胞吸收时，不会形成任何功能药物，因此使用这种方法进行治疗的不良影响应该是最小的。因此，与直接传递siRNAs或shRNAs相比，该方法具有两个优点：降低毒性以及通过扩增机制提高效力。该策略不需要基因治疗，有可能扩展到针对大多数(如果不是全部)RNA病毒。 项目简介：丙型肝炎病毒(丙型肝炎病毒)感染了大约2-4%的美国人口和全球超过1.7亿人，并可能导致肝硬化或肝癌。没有疫苗，目前的治疗方法往往无效，并有严重的副作用。虽然使用RNA干扰的潜在新疗法已经引起了一些兴奋，但它们目前的效力有限。这项拟议的研究将探索一种治疗丙型肝炎病毒和许多其他RNA病毒的新方法，该方法可能通过使用一种机制来放大药物在受感染细胞中的作用，从而克服效力限制。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infects more than 170 million people worldwide and is the leading condition requiring liver transplantation. There is no vaccine and current treatments are often ineffective and have severe side-effects. There is currently considerable interest in the use of RNA interference as an antiviral modality. Although both siRNAs and shRNA can be highly potent, with IC50s in the subnanomolar range, the ability to deliver effective amounts of an RNA drug to infected hepatocytes in the liver limits efficacy. Hence, absent a breakthrough in delivery technology, si/shRNAs with still higher potency are needed if they are to be clinically useful. In addition, while delivery to the liver by an intravenous route is easier than for many other tissues, every delivery mode allows some uptake by other organs, leading to potential adverse effects in uninfected tissues. Here we propose a novel approach in which limited intracellular delivery is compensated by a mechanism for production of many shRNAs from each therapeutic molecule. Moreover, the production of shRNAs occurs only in cells infected by HCV. Hence the therapeutic molecule can be designed to target either a viral or a host gene, resulting in either suppression of viral growth or death of the infected cell (or both in a combination therapy). No functional drug is formed when the agent is taken up by uninfected cells, so adverse effects from a treatment using this approach should be minimal. Thus, the method provides two advantages over direct delivery of siRNAs or shRNAs: reduced toxicity as well as increased potency through an amplification mechanism. The strategy, which does not require gene therapy, can potentially be extended to targeting most if not all RNA viruses. Project Narrative: Hepatitis C virus (HCV) infects some 2-4% of the US population and more than 170 million people worldwide and can lead to cirrhosis or liver cancer. There is no vaccine and current treatments are often ineffective and have severe side-effects. While potential new treatments using RNA interference have generated some excitement, they are currently limited in potency. The proposed study will investigate a novel therapeutic approach to HCV and many other RNA viruses that has the potential to overcome the potency limitation by using a mechanism for amplifying the effects of the drug specifically in infected cells.