HAIRPIN RIBOZYME GENE THERAPY FOR HCV INFECTION

HCV 感染的发夹核酶基因疗法

• 批准号: 2536407
• 负责人: JACK R BARBER
• 金额: $ 7.02万
• 依托单位: ITHERX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2536407
• 关键词: Adenoviridae; RNase protection assay; adeno associated virus group; antiviral agents; chemical synthesis; enzyme activity; gene therapy; hepatitis C; hepatitis C virus; molecular cloning; ribozymes; tissue /cell culture; transfection; transfection /expression vector; virus RNA; western blottings

Hepatitis C virus (HCV) is the major cause of non-A, non-B hepatitis, which is a serious worldwide health problem. Our long term objective is to develop hairpin Ribozyme (Rz) gene therapy for the treatment of HCV infection. Immusol's Rz core technology, developed as a result of the success of its HIV program, is based upon the ability to engineer and optimize hairpin Rz genes whose transcribed RNAs can specifically degrade almost any undesirable RNA molecule. HCV is especially suited for ribozyme-mediated therapy since the viral genome is present exclusively in the form of RNA. HCV encodes only one primary transcript, thus, cleavage of any target sequence within this RNA should abolish virus expression. Immusol has generated two hairpin ribozymes target at HCV (+) strand RNA as potential therapeutic agents for HCV infection (Gene Therapy, 1996, 3: 994). Immusol also plans to target the negative strand RNA that is an essential intermediate in HCV replication. Degradation of this RNA may be more effective, since its intracellular level is lower than that of the positive strand RNA. Therefore, we propose a Phase I SBIR studies aimed at: 1) to synthesize and optimize effective ribozymes that target HCV positive- (+) and negative- (-) strand RNA; 2) to generate viral vectors (AV and AAV) that express active hairpin ribozymes; and 3) to test vector- derived ribozyme activity in reducing HCV gene expression in liver cell culture Achieving these three Aims will generate the most effective ribozyme viral vector(s) for preclinical studies. PROPOSED COMMERCIAL APPLICATION: Immusol plans to commercially develop a Rz gene therapy approach to HBV infection. We will manufacture and provide Rz-expressing viral vectors in a vial. The vectors will then be provided to medical centers around the world that will carry out the in vivo vector-mediated gene transfer into patient liver cells to combat HBV virus.

丙型肝炎病毒(丙型肝炎)是非甲非乙型肝炎的主要原因， 这是一个严重的世界性健康问题。我们的长期目标是 发夹状核酶(Rz)基因治疗丙型肝炎病毒 感染。Immusol的Rz核心技术，作为 它的艾滋病毒项目的成功，是基于设计和开发 优化其转录的RNA可特异性降解的发夹Rz基因 几乎所有不受欢迎的RNA分子。丙型肝炎病毒特别适合于 核酶介导的治疗因为病毒基因组只存在于 核糖核酸的形式。丙型肝炎病毒只编码一个初级转录本，因此，裂解 这种RNA中的任何靶序列的结合都应该消除病毒的表达。 免疫系统已经产生了两个针对丙型肝炎病毒(+)链RNA的发夹状核酶 作为潜在的丙型肝炎病毒感染治疗剂(基因治疗，1996，3： 994)。Immusol还计划针对负链RNA，它是一种 丙型肝炎病毒复制的重要中间体。这种RNA的降解可能是 更有效，因为它的细胞内水平低于 正链RNA。因此，我们建议进行第一阶段SBIR研究，目的是 AT：1)合成和优化靶向丙型肝炎病毒的有效核酶 正(+)和负(-)链RNA；2)构建病毒载体 (AV和AAV)表达活性发夹状核酶；以及3)测试载体- 衍生核酶降低丙型肝炎病毒基因在肝细胞中表达的活性 实现这三个目标的文化将产生最有效的 核酶病毒载体(S)用于临床前研究。 建议的商业应用： Immusol计划商业化开发一种针对乙肝病毒的Rz基因疗法 感染。我们将制造和提供表达Rz的病毒载体 一小瓶。然后，病媒将被提供给各地的医疗中心 将在体内进行载体介导的基因转移到 病人的肝细胞可以对抗乙肝病毒。