Treatment of HCV infection by microRNA clusters in HCV/HIV co-infected drug users

MicroRNA簇治疗HCV/HIV共感染吸毒者的HCV感染

• 批准号: 8262591
• 负责人: Marc J Thibonnier
• 金额: $ 18.18万
• 依托单位: AMERICAN GENE TECHNOLOGIES INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2012-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262591
• 关键词: 3' Untranslated Regions; 5' Untranslated Regions; Acquired Immunodeficiency Syndrome; Adherence; Antiviral Agents; CD81 gene; Cell Culture Techniques; Cells; Cessation of life; Chronic; Cities; Clinical; Companions; Computer Simulation; Diagnosis; Disease; Docking; Drug Interactions; Drug user; Engineering; Epidemic; Event; Genes; Genome; Goals; HIV; HIV-1; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Hepatotoxicity; Human; Illicit Drugs; Immune response; In Vitro; Incidence; Individual; Infection; Injecting drug user; Injury; Interferons; Intervention; Joints; Learning; Lentivirus Vector; Life Cycle Stages; Liver; Medical; Metabolic; MicroRNAs; Modeling; Monitor; Morbidity - disease rate; Opportunistic Infections; Outcome; Pathology; Patients; Phase; Proteins; Public Health; RNA replication; Regimen; Research; Research Project Grants; Resistance; Risk; SR-BI receptor; Small Business Innovation Research Grant; Testing; Therapeutic; Time; Toxic effect; Treatment Protocols; Universities; Vesnarinone; Viral; Virus; anti-hepatitis C; antiretroviral therapy; claudin-1 protein; cost; design; experience; gene therapy; high risk; improved; in vitro testing; in vivo; innovation; mimetics; mortality; mutant; occludin; prevent; research and development; research study; response; success; transmission process; uptake; vector; viral RNA; virus envelope

DESCRIPTION (provided by applicant): The goal of this research project is to develop an innovative yet simple therapeutic strategy to eradicate HCV infection early on in HCV infected or HCV/HIV co-infected injecting drug users (IDUs) by engineering lentiviral vectors (LVs) expressing microRNA clusters in the liver. Specifically, we plan to simultaneously inhibit several steps of the HCV life cycle by purposely targeting various segments of the HCV gene and its host cell companion proteins. LVs targeting the liver will be built to deliver three microRNA clusters aiming at: 1. Blockade of HCV docking and entry into hepatocytes by a microRNA cluster targeting the HCV envelope and four host proteins (scavenger receptor B1, CD81, claudin-1 and occludin) involved in HCV entry into hepatocytes 2. Direct suppression of HCV RNA replication by a microRNA cluster targeting various sections (5'UTR, 3'UTR, structural and non-structural regions) of the HCV genome 3. Interferon-mimetic suppression of the HCV life cycle by a microRNA cluster specifically targeting various sections of the HCV genome known to be the targets on interferon-induced microRNAs This "cluster attack" on the HCV genome may particularly benefit injecting drug users (IDUs) infected with HCV or HIV/HCV because of the more severe course of their diseases, their more limited and often delayed treatment, their poor adherence to current treatments, and higher risk of emergence of resistant HCV strains. Barriers to HCV diagnosis, assessment, treatment, and monitoring as well as considerable treatment- related toxicities result in extremely low treatment uptake and success among IDUs with the currently available therapies. However, improved clinical outcomes occur after successful treatment in patients who achieve a sustained virologic response (SVR). For difficult-to-treat IDUs, we propose to achieve SVR and possible virus eradication by one time systemic delivery to the liver of several miRNAs. This offers the advantage of a simplified yet effective regimen, very few medical interventions, and reduced toxicities and cost. Targeting diferent viral functionalities may dramatically prolong viral suppression and decrease the likelihood of escape as suggested for the HIV-1 virus. Furthermore, such treatment should reduce the significant morbidity and mortality observed in IDUs co- infected with HCV and HIV. ! PUBLIC HEALTH RELEVANCE: There is a pressing need to develop a curative treatment for hepatitis C virus (HCV) infection, an epidemic afflicting 180 million individuals worldwide. Barriers to HCV diagnosis, assessment, treatment, and monitoring as well as considerable treatment-related toxicities result in extremely low treatment uptake and success among injecting drug users (IDUs) infected with HCV or co- infected with HCV and HIV. The goal of this research project is to develop an innovative yet simple therapeutic strategy to eradicate HCV infection early on in HCV or HCV/HIV co-infected IDUs by engineering lentiviral vectors expressing microRNA clusters in the liver.

描述（由申请人提供）：本研究项目的目标是开发一种创新而简单的治疗策略，通过在肝脏中表达microRNA簇的慢病毒载体（lv）工程设计，在HCV感染或HCV/HIV合并感染的注射吸毒者（IDUs）中早期根除HCV感染。具体来说，我们计划同时抑制几种