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：
10400202
负责人：
Bing Yao
金额：
$ 38.75万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400202
关键词：
Address Adult Age Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Behavior Animal Model Behavior Brain Brain Diseases CAG repeat CRISPR/Cas technology Cells Clinic Corpus striatum structure Disease Embryo Future Gene Targeting Genes Genome Guide RNA Half-Life Human Huntington Disease Huntington gene Injections Knock-in Mouse Lead Long-Term Effects Longitudinal Studies Modification Monkeys Mosaicism Motor Mus Mutate Mutation Nerve Degeneration Neurodegenerative Disorders Neurologic Symptoms Neurons Parkinson Disease Patients Phase Proteins Reporting Safety Signal Transduction Technology Testing Therapeutic Effect Toxic effect Ubiquitin Wild Type Mouse Yang adeno-associated viral vector brain behavior brain morphology cell type disease-causing mutation effective therapy mutant nervous system disorder neuropathology neurotoxicity new technology phase 1 study phase 2 study polyglutamine protein misfolding safety testing side effect therapeutically effective tool treatment strategy vector

项目摘要

Use of CRISPR/Cas9 to treat Huntington disease Summary A variety of neurological diseases are caused by the 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 disease, the CAG repeat expansion in exon1 of the huntingtin gene leads to selective neurodegeneration and progressive neurological symptoms, which are incurable with the 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 the neurotoxicity and neurological symptoms in Huntington 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 the adult mouse brains in phase 1 studies. The phase 2 studies will rigorously examine the long-term effects of removing mutant huntingtin in Huntington 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 clinic use of CRISPR/Cas9 to ameliorate neurological symptoms in brain diseases.

使用 CRISPR/Cas9 治疗亨廷顿病概括多种神经系统疾病是由疾病基因突变引起的，这些突变会导致神经系统疾病的发生。大脑中的毒性。降低或阻断突变基因的表达被认为是一种有效的治疗方法治疗这些神经系统疾病的策略。在亨廷顿病中，CAG 重复扩增亨廷顿基因的外显子 1 会导致选择性神经变性和进行性神经系统症状，目前的疗法无法治愈。我们将使用新开发的技术 CRISPR/Cas9 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 在减轻亨廷顿神经毒性和神经系统症状方面的良好效果病鼠。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调查。目前的申请将检查修饰后的Cas9的基因打靶效率在第一阶段研究中的成年小鼠大脑中。第二阶段研究将严格检查长期影响去除亨廷顿病小鼠中的突变亨廷顿蛋白以及 CRISPR/Cas9 引起的潜在副作用。鉴于使用 CRISPR/Cas9 去除大脑中突变基因以治疗多种疾病的需求不断增加神经系统疾病，我们的研究将对 CRISPR/Cas9 的未来临床使用产生广泛的影响改善脑部疾病的神经症状。