Modeling HIV-1 siRNA Therapy

HIV-1 siRNA 治疗建模

• 批准号: 6701291
• 负责人: IRVIN S.Y. CHEN
• 金额: $ 30.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6701291
• 关键词: AIDS therapy; Lentivirus; Macaca mulatta; RNA interference; SCID mouse; biotechnology; clinical research; embryo /fetus cell /tissue; gene delivery system; gene therapy; human immunodeficiency virus 1; human tissue; nonhuman therapy evaluation; small interfering RNA; tissue /cell culture; transfection /expression vector; virus replication

DESCRIPTION (provided by applicant): The overall hypothesis to be tested in this proposal is that small interfering RNAs directed to HIV-1 can serve as a therapy for HIV-1 disease. RNA interference is an evolutionarily conserved mechanism whereby small double stranded RNAs induce sequence specific silencing of homologous genes. The application of siRNA technology consists of chemical or recombinant 21- 29 nucleotide length double strand RNAs that act to degrade the RNA template to which it has homology, siRNAs have been utilized for "knock-out" of various cellular genes. Recently siRNA directed to HIV-1 sequences have been shown to inhibit HIV-1 replication in cell culture. Other "genetic immunization" approaches to HIV-1 disease successfully inhibited HIV-1 in cell culture, but extension of the studies to humans had resulted in minimal efficacy. It is unclear whether the lack of success is due to the gene therapeutic reagent itself, the delivery system, or both. Thus, it is critical that genetic immunization approaches be thoroughly modeled in systems where variables can be tested and optimized to gain an understanding of the most effective parameters for inhibition. We propose to model siRNA to HIV-1 and CCR5 using lentiviral vectors for stable delivery.

描述（由申请人提供）： 在该提案中要检验的总体假设是，针对HIV-1的小干扰RNA可以作为HIV-1疾病的疗法。 RNA干扰是一种进化保守的机制，其小双链RNA诱导同源基因的序列特异性沉默。 siRNA技术的应用由化学或重组21-29核苷酸长度双链RNA组成，可用于降解其具有同源性的RNA模板，SIRNA被用于各种细胞基因的“敲除”。最近，针对HIV-1序列的siRNA已被证明可以抑制细胞培养中的HIV-1复制。 HIV-1疾病的其他“遗传免疫”方法成功地抑制了细胞培养中的HIV-1，但研究向人类的扩展导致了最低的疗效。目前尚不清楚缺乏成功是由于基因治疗试剂本身，递送系统还是两者兼而有之。因此，至关重要的是，在可以测试和优化变量以了解最有效参数的抑制参数的系统中，对遗传免疫方法进行彻底建模。我们建议使用慢病毒向量对HIV-1和CCR5进行建模，以稳定递送。