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.

项目概要项目 3 (HD) 亨廷顿病 (HD) 是一种常染色体显性遗传疾病，其特征是纹状体神经元缺失中枢神经系统，与进行性不必要的舞蹈动作、行为和精神障碍和痴呆1,2。 HD 是由第一个外显子中的 CAG 三联体重复扩增引起的编码亨廷顿蛋白的 HTT 基因，导致谷氨酰胺 (polyQ) 延伸。高清影响所有种族群体，平均发病率为每 10 万人中约 5 例，但患病率可能有所不同人群中约 10 倍。目前 HD 还没有治愈或有效的治疗方法，尽管有些治疗干预可能会减轻患者症状的严重程度，HD 通常会导致 10 年内死亡发病30年。在这个后续项目中，我们的目标是改善 HD 蛋白表达，以挽救 HD 疾病进展患者。具体来说，我们的目标是：（1）优化碱基编辑和主编辑策略以纠正高清重复扩张; (2) 优化 AAV 交付，以实现基本编辑器和主要编辑器介导的 HD 扩展校正老鼠； (3) 大规模开展临床前研究（JAX）。我们将与基因编辑核心密切合作，开发高清模型系统中最新的基础编辑和/或主要编辑技术。我们将迭代基因编辑核心，确保我们的基因组编辑工具最大限度地提高靶向编辑效率，最大限度地减少不良的基因编辑副产物和脱靶编辑事件，并最大限度地提高与体内的兼容性具有潜在治疗相关性的递送方法。