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Use of CRISPR/Cas9 to Treat Huntington Disease

使用 CRISPR/Cas9 治疗亨廷顿病

基本信息

批准号：
10374293
负责人：
Bing Yao
金额：
$ 39.08万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374293
关键词：
Use CRISPR Cas9 Treat Huntington

项目摘要

A variety of neurological diseases are caused by mutations in the disease genes that result in gain-of-toxicity in the brain. Lowering or blocking the expression of mutant genes is considered an effective therapeutic strategy for the treatment of these neurological disorders. In Huntington’s disease, the CAG repeat expansion in exon1 of the huntingtin gene leads to selective neurodegeneration and progressive neurological symptoms, which are incurable with current therapies. We will use a newly developed technology, CRISPR/Cas9, to eliminate the expression of mutant huntingtin in Huntington disease mice. Our preliminary studies have shown the promising effect of CRISPR/Cas9 to alleviate neurotoxicity and neurological symptoms in Huntington’s disease mice. However, the long-term effects of CRISPR/Cas9 and the safety issue of this new technology remain to be investigated. The current application will examine the gene targeting efficiency of modified Cas9 in adult mouse brains in R21 studies. The R33 studies will rigorously examine the long-term effects of removing mutant huntingtin in Huntington’s disease mice and potential side effects caused by CRISPR/Cas9. Given the increasing demand to use CRISPR/Cas9 to remove mutant genes in the brain to treat a variety of neurological disorders, our studies will have broad implications for the future clinical use of CRISPR/Cas9 to ameliorate neurological symptoms in brain diseases.

多种神经系统疾病是由疾病基因突变引起的，导致大脑中的毒性获得。降低或阻断突变基因的表达被认为是治疗这些神经系统疾病的有效治疗策略。在亨廷顿氏病中，亨廷顿基因外显子1中的CAG重复扩增导致选择性神经变性和进行性神经症状，这是用目前的疗法无法治愈的。我们将使用一种新开发的技术CRISPR/Cas9来消除亨廷顿病小鼠中突变亨廷顿蛋白的表达。我们的初步研究显示了CRISPR/Cas9在缓解亨廷顿病小鼠的神经毒性和神经症状方面的有希望的效果。然而，CRISPR/Cas9的长期效果以及这项新技术的安全性问题仍有待研究。当前的申请将在R21研究中检查修饰的Cas9在成年小鼠大脑中的基因靶向效率。R33研究将严格检查在亨廷顿病小鼠中去除突变亨廷顿蛋白的长期影响以及CRISPR/Cas9引起的潜在副作用。鉴于越来越多的人需要使用CRISPR/Cas9来去除大脑中的突变基因以治疗各种神经系统疾病，我们的研究将对CRISPR/Cas9未来临床应用产生广泛的影响，以改善脑部疾病的神经系统症状。