Gene Therapy for Huntingtons Disease by RNA interference

RNA干扰亨廷顿病基因治疗

• 批准号: 6792553
• 负责人: GUSTAVO TISCORNIA
• 金额: $ 4.73万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6792553
• 关键词: Huntington' s disease; Lentivirus; RNA interference; behavior test; biotechnology; brain; gene induction /repression; gene therapy; genetic promoter element; genetically modified animals; green fluorescent proteins; injection /infusion; laboratory mouse; nonhuman therapy evaluation; postdoctoral investigator; small interfering RNA; transfection; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): Lentiviral vectors are potent vehicles for gene delivery. RNAi has recently emerged as a novel, evolutionarily conserved pathway by which specific genes can be down regulated. We are currently working in the development of lentiviral vectors carrying poll promoters capable of driving the expression of small interfering RNAs (siRNAs); we have successfully achieved specific and stable down regulation of a number of genes both in vitro and in vivo using such vectors. Huntington's disease (HD) is an inherited neurodegenerative disease caused by a gain of function CAG triplet repeat expansion in exon 1 of huntingtin, a gene of uncertain function. We propose to develop lentiviral mediated siRNAs against huntingtin and characterize the vectors in vitro and in vivo. In particular we will seek in vivo proof of principle that disease progression in a transgenic mouse model of HD can be halted or retarded by this approach. We will do this monitoring disease progression after a) direct injection of lentiviral siRNA vectors into the brain and b) generating a double transgenic mouse with both the huntingtin transgene and an anti-huntingtin lentiviral silencing cassette.

描述(由申请人提供)： 慢病毒载体是基因传递的有效载体。RNAi最近已经成为一种新的、进化上保守的途径，通过它可以下调特定基因的表达。我们目前正在开发携带Poll启动子的慢病毒载体，能够驱动小干扰RNA(SiRNAs)的表达；我们已经成功地在体外和体内实现了对一些基因的特异和稳定的下调。亨廷顿病是一种遗传性神经退行性疾病，由功能未知的亨廷顿蛋白基因第一外显子CAG三联体重复扩增所致。我们建议开发慢病毒介导的针对亨廷顿蛋白的siRNAs，并对其进行体外和体内鉴定。特别是，我们将寻求体内证据，证明这种方法可以阻止或延缓HD转基因小鼠模型的疾病进展。我们将在a)将慢病毒siRNA载体直接注射到大脑中，以及b)产生同时带有Huntingtin转基因和抗Huntingtin慢病毒沉默盒的双重转基因小鼠后，监测疾病的进展。