Project 3: Therapeutic Gene Editing for Huntington's Disease

项目3：亨廷顿病的治疗性基因编辑

基本信息

批准号：
10668769
负责人：
DAVID R LIU
金额：
$ 67.03万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-16 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668769
关键词：
Acceleration Adolescent Adverse event Affect Alleles Animal Model Behavioral Biodistribution Biological Models CAG repeat Capsid Cell model Cells Central Nervous System Clinic Clustered Regularly Interspaced Short Palindromic Repeats Code Corpus striatum structure Dementia Disease Disease Progression Disease model Dose Ethnic Population Event Exons Gene Expression Gene Proteins Genes Genome Genomics Glutamine Goals Human Huntington Disease Huntington gene Incidence Interruption Investigation Investigational Drugs Lead Life Expectancy Mediating Methods Modification Motor Movement Mus Neurons Newborn Infant Onset of illness Outcome Pathogenicity Patients Persons Population Prevalence Research Personnel Resources Route Safety Severities Stretching Symptoms Technology Therapeutic Therapeutic Intervention Tissues Trinucleotide Repeats Triplet Multiple Birth Work adeno-associated viral vector autosome base editing base editor cognitive disability design disease phenotype effective therapy genome editing improved in vivo indexing innovation knock-down lead candidate nervous system disorder polyglutamine pre-clinical preclinical development preclinical safety preclinical study prime editing prime editor protein expression psychiatric disability therapeutic development therapeutic gene therapeutic genome editing tool transcriptomics vector

项目摘要

PROJECT SUMMARY PROJECT 3 (HD) Huntington Disease (HD) is an autosomal dominant disorder characterized by the loss of striatal neurons in the central nervous system and is associated with progressive unwanted choreatic movements, behavioral and psychiatric disturbances, and dementia1,2. HD is caused by CAG triplet repeat expansions in the first exon of the HTT gene which codes for huntingtin protein, resulting in an expanded stretch of glutamines (polyQ). HD affects all ethnic groups with an average incidence of ~5 per 100,000 people, though the prevalence can vary by ~10 fold among populations. There is currently no cure or effective treatment for HD and while some therapeutic interventions may lessen the severity of patient symptoms, HD typically results in fatality within 10- 30 years of disease onset. In this follower project, we aim to improve HD protein expression to enable rescue of disease progression in HD patients. Specifically, we aim to: (1) Optimize base editing and prime editing strategies to correct HD repeat expansion; (2) Optimize AAV delivery for base and prime editor-mediated correction of the HD expansion in mice; (3) Conduct pre-clinical studies at scale (JAX). We will work closely with the Gene Editing Core to develop the latest base editing and/or prime editing technologies in HD model systems. We will iterate with the Gene Editing Core to ensure that our genome editing tools maximize on-target editing efficiencies, minimize undesirable gene editing byproducts and off-target editing events, and maximize compatibility with in vivo delivery methods of potential therapeutic relevance.

项目摘要项目3（HD）亨廷顿疾病（HD）是一种常染色体显性疾病，其特征是纹状体神经元失去中枢神经系统，与进行性不必要的绒毛运动，行为和精神病障碍和痴呆1,2。高清是由CAG三胞胎重复扩展引起的。编码亨廷汀蛋白的HTT基因，导致扩大的谷氨酰胺（Polyq）。高清影响所有种族，平均发生率为每10万人约5人，尽管患病率可能会有所不同人口中的约10倍。目前尚无HD治疗或有效的治疗方法治疗性干预措施可能会减轻患者症状的严重程度，HD通常导致10-内死亡 30年的疾病发作。在这个追随者项目中，我们旨在改善HD蛋白表达以挽救HD的疾病进展患者。具体来说，我们的目标是：（1）优化基础编辑和主要编辑策略以纠正高清重复扩张; （2）优化基础和主要编辑介导的HD扩展校正的AAV输送小鼠；（3）按比例进行临床前研究（JAX）。我们将与基因编辑核心紧密合作以发展高清模型系统中的最新基础编辑和/或主要编辑技术。我们将用基因迭代编辑核心，以确保我们的基因组编辑工具最大化目标编辑效率，最小化不良基因编辑副产品和脱靶编辑事件，并最大程度地兼容体内潜在治疗相关性的输送方法。