Selective Editing of the Mutant Huntingtin Gene

突变亨廷顿基因的选择性编辑

基本信息

批准号：
9906917
负责人：
NEIL ARONIN
金额：
$ 46.53万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906917
关键词：
Affect Age Alleles Amyotrophic Lateral Sclerosis Animal Model Antisense Oligonucleotides Behavioral Brain Diseases Brain region CAG repeat CRISPR/Cas technology Care given by nurses Characteristics Child Clustered Regularly Interspaced Short Palindromic Repeats Code DNA Binding Domain Data Dementia Detection Development Diagnosis Discipline of Nursing Disease Dyskinetic syndrome Economic Burden Economics Endonuclease I Equilibrium Exons Family Frameshift Mutation Frontotemporal Dementia Genes Genetic Genetic Polymorphism Genetic Transcription Goals Gross National Product Guide RNA Head Health Benefit Heterozygote Human Human Cell Line Huntington Disease Huntington gene Huntington protein Impaired cognition Individual Inherited Knock-in Knock-in Mouse Laboratories Length Measurement Mental Depression Messenger RNA MicroRNAs Modeling Movement Movement Disorders Mus Mutation Neostriatum Nerve Degeneration Neurons Nuclear Outcome Parents Pathogenesis Pathogenicity Pathologic Patients Production Protein Fragment Proteins Public Health Publishing Single Nucleotide Polymorphism Small Interfering RNA Societies Stress Testing Therapeutic Time Untranslated Regions Western Blotting Work base improved in vivo mRNA Surveillance motor impairment mouse model mutant nervous system disorder neuropathology novel nuclease prevent programs promoter public health relevance repaired success

项目摘要

The cause of Huntington’s disease is an increase in the trinucleotide CAG repeat from under 36 repeats to 36 or greater repeats. The mode for the number of repeats is 42, and most patients have between 40 and 45. The disease generally starts between ages 30 and 40, with onset and progression of impaired cognition, depression, and aberrant movement. The genetics is autosomal dominant. With gene editing, we aim to eliminate expression of the mutant allele of Huntington’s disease or repair the mutation by reducing the number of CAG repeats. We will use CRISPR-Cas9 for selective targeting of single nucleotide polymorphisms with heterozygosities to prevent the mutant huntingtin allele from producing protein. Generating frameshift mutations at the SNP heterozygosity reduces mutant huntingtin protein, with no production of mutant protein fragments. In a second approach, we reduce the number of CAG repeats from a high number in the mutant allele to a healthy number of CAG repeats, through the use of Cas9 nickases. The nickase Cas9D10A is used to reduce the CAG repeat number below the pathogenic threshold. We have preliminary data that supports each aspect of the proposal. The goal of this discovery application is to set the stage for promising therapeutics for treatment of Huntington’s disease and other autosomal dominant neurological disorders caused by trinucleotide CAG repeat expansions.

亨廷顿氏病的原因是三分之一以下的三核苷酸CAG重复的增量重复重复36或更高的重复模式。 40和45。疾病一般星星从30至40岁开始，发作和受损的进展认知，抑郁和异常运动。旨在消除亨廷顿氏病突变等位基因的表达或通过降低您的突变来修复突变 CAG重复数量。产生蛋白质的杂合子对突变的等位基因 SNP杂合子的突变可降低突变蛋白蛋白，而没有产生突变蛋白片段。通过使用cas9 nick来进行健康数量的CAG重复。将CAG重复数减少到病原阈值以下。提案的方面。治疗亨廷顿病和其他常染色体显性神经系统疾病三核苷酸CAG重复扩展。