Use of CRISPR/Cas9 to Treat Huntington Disease

多种神经系统疾病是由疾病基因的突变引起的，这些突变导致大脑毒性的增加。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，亨廷顿蛋白基因外显子1的CAG重复扩增导致选择性神经变性和进行性神经症状，这是目前治疗无法治愈的。我们将使用新开发的技术CRISPR/Cas9来消除亨廷顿病小鼠中突变亨廷顿蛋白的表达。我们的初步研究表明，CRISPR/Cas9在缓解亨廷顿舞蹈病小鼠的神经毒性和神经系统症状方面具有良好的效果。然而，CRISPR/Cas9的长期影响和这项新技术的安全性问题仍有待研究。目前的申请将在R21研究中检测修饰Cas9在成年小鼠脑中的基因靶向效率。R33研究将严格检查去除突变亨廷顿蛋白对亨廷顿病小鼠的长期影响以及CRISPR/Cas9引起的潜在副作用。鉴于使用CRISPR/Cas9去除大脑中的突变基因来治疗各种神经系统疾病的需求日益增加，我们的研究将对未来临床使用CRISPR/Cas9来改善脑部疾病的神经系统症状具有广泛的意义。

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.