Project 3: Therapeutic Gene Editing for Huntington's Disease

项目总结项目3(高清版) 亨廷顿病(HD)是一种常染色体显性遗传病，其特征是纹状体神经元的丢失。 中枢神经系统，并与进行性有害的舞蹈动作、行为和 精神障碍和痴呆1，2.HD是由CAG三联体重复扩增引起的 HTT基因编码亨廷顿蛋白，导致谷氨酸的扩展(PolyQ)。高清 影响所有种族，平均发病率为每10万人约5例，尽管患病率可能有所不同 在人群中增加了约10倍。目前还没有治愈或有效的治疗HD的方法，虽然有些 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- 发病30年。 在这个追随者项目中，我们的目标是改善HD蛋白的表达，从而能够挽救HD的疾病进展 病人。具体地说，我们的目标是：(1)优化基础编辑和主要编辑策略，以纠正HD重复 扩展；(2)优化基础和主要编辑调解的高清扩展的AAV交付 (3)开展规模临床前研究(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本编辑和/或主要编辑技术。我们将与基因一起迭代 编辑核心以确保我们的基因组编辑工具最大限度地提高目标编辑效率，最大限度地减少 不受欢迎的基因编辑副产品和脱靶编辑事件，并最大限度地与体内兼容 具有潜在治疗意义的给药方法。

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.