Project 3: Therapeutic Gene Editing for Huntington's Disease

项目3（HD） 亨廷顿舞蹈病（HD）是一种常染色体显性遗传疾病，其特征在于纹状体神经元的缺失， 中枢神经系统，并与渐进的不必要的舞蹈病运动，行为和 精神障碍和痴呆症1，2。HD是由第一外显子中CAG三联重复扩增引起的， 编码亨廷顿蛋白的HTT基因，导致谷氨酰胺（polyQ）的延伸。HD 影响所有种族群体，平均发病率约为每100，000人5例，尽管患病率可能有所不同 在人群中增加了约10倍。目前没有治愈或有效的治疗HD，而一些 治疗性干预可减轻患者症状的严重程度，HD通常在10 - 20分钟内导致死亡。 发病30年。 在这个后续项目中，我们的目标是提高HD蛋白的表达，使救援的疾病进展，在HD 患者具体而言，我们的目标是：（1）优化基础编辑和引物编辑策略，以纠正HD重复 （2）优化AAV递送，用于在扩增中的HD扩增的碱基和引物编辑介导的校正。 小鼠;（3）进行大规模临床前研究（JAX）。我们将与基因编辑核心密切合作， HD模型系统中最新的基础编辑和/或主要编辑技术。我们将与基因 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， 不希望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 潜在治疗相关性的递送方法。

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.