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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）