An RNAi Trojan Horse for treatment of hepatitis C.

用于治疗丙型肝炎的 RNAi 特洛伊木马。

• 批准号: 7575206
• 负责人: Brian H. Johnston
• 金额: $ 30万
• 依托单位: SOMAGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7575206
• 关键词: Adverse effects; American Society of Hematology; Animals; Antiviral Agents; Cells; Cessation of life; Chemicals; Cirrhosis; Collaborations; Combined Modality Therapy; DNA; Development; Dicer Enzyme; Equus caballus; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genome; Goals; Growth; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; In Situ; In Vitro; Intravenous; Lead; Letters; Liver; Luciferases; Malignant neoplasm of liver; Mammalian Cell; Methods; Modality; Modification; Northern Blotting; Organ; Patients; Pegylated Interferon Alfa; Pharmaceutical Preparations; Phase; Polymerase; Population; Process; Prodrugs; Production; Property; Proteins; RNA; RNA Interference; RNA Precursors; RNA Viruses; RNA chemical synthesis; RNA-Directed RNA Polymerase; Reaction; Recombinants; Replicon; Reporter; Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Reverse Transcription; Ribavirin; Role; Route; Small Interfering RNA; System; Technology; Testing; Therapeutic; Tissues; Toxic effect; Transcript; Universities; Vaccines; Viral; Virus; base; cost; design; drug candidate; expression vector; gene therapy; human DICER1 protein; improved; interest; liver transplantation; novel strategies; novel therapeutic intervention; nuclease; premature; small hairpin RNA; standard of care; success; uptake; viral RNA

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.

描述（由申请人提供）：丙型肝炎病毒（HCV）感染全球超过1.7亿人，是需要肝移植的主要疾病。目前还没有疫苗，目前的治疗方法往往无效，而且有严重的副作用。目前有相当大的兴趣使用RNA干扰作为抗病毒方式。尽管sirna和shRNA都是非常有效的，ic50在亚纳摩尔范围内，但将有效量的RNA药物递送到肝脏中受感染的肝细胞的能力限制了疗效。因此，在递送技术没有突破的情况下，如果要使si/ shrna在临床上发挥作用，就需要更高效力的si/ shrna。此外，虽然通过静脉途径将药物输送到肝脏比许多其他组织更容易，但每种输送方式都会使其他器官吸收一些药物，从而导致未感染组织产生潜在的不良影响。在这里，我们提出了一种新的方法，在这种方法中，有限的细胞内递送通过从每个治疗分子中产生许多shrna的机制来补偿。此外，shrna的产生只发生在被HCV感染的细胞中。因此，治疗分子可以设计为针对病毒或宿主基因，从而抑制病毒生长或导致感染细胞死亡（或在联合治疗中两者都有）。当药物被未感染的细胞吸收时，不会形成功能性药物，因此使用这种方法治疗的副作用应该是最小的。因此，与直接递送sirna或shrna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。这种策略不需要基因治疗，可以扩展到针对大多数RNA病毒，如果不是全部的话。