Development of miCas9 mediated gene editing therapies for cystic fibrosis

miCas9介导的囊性纤维化基因编辑疗法的开发

• 批准号: 10811304
• 负责人: JIE XU
• 金额: $ 24.61万
• 依托单位: GENETOBE INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10811304
• 关键词: Development; miCas9; mediated; gene; editing

Project Summary Cystic Fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The disease affects multiple organs, with lung disease producing most CF morbidity and mortality. Major progress has been made over the past decade in CF drug development. Greater than 90% patients now benefit from mono or combination therapy of several CFTR potentiators and correctors. However, these compounds neither permanently cure the disease nor address the unmet need of the 10% null mutation carriers. Gene editing therapy (GETx) represents a promising strategy to permanently cure the disease. In 2019 we reported efficient gene editing on major CFTR loci in human induced pluripotent stem (iPS) cells. In 2020, we reported the development of mi-spCas9 that has extraordinary homology directed repair capacity. Built on these two major lines of work, here we propose to develop and optimize a novel mi-saCas9 variant that is suitable for in vivo GETx of CF. In Aim 1, we will develop mi-saCas9-KKH-A that is particular useful for correcting CF-causing CFTR mutations. In Aim 2 we will test two GETx strategies for CF: (i) a large size gene knock-in strategy that is suitable for correcting all CFTR mutations; and (ii) a donor free strategy that is suitable for correcting compound heterozygous CFTR mutations. Successful completion of the proposed Phase I work will set a solid foundation for Phase II, in which we plan to evaluate the efficacy and safety of the mi-saCas9-KKH-A based GETx strategies in preclinical CF animal models.

项目摘要 囊性纤维化（CF）是由囊性纤维化跨膜突变引起的遗传疾病 电导调节剂（CFTR）基因。该疾病影响多个器官，肺部疾病 产生大多数CF发病率和死亡率。在过去的十年中取得了重大进展 在CF药物开发中。现在大于90％的患者从单声道或组合中受益 几个CFTR增强剂和校正器的治疗。但是，这些化合物都不 永久治愈该疾病，也无法满足10％无效突变载体的需求。 基因编辑疗法（GETX）代表了永久治愈该疾病的有前途的策略。 2019年，我们报告了人类诱导的多能茎的主要CFTR基因座的有效基因编辑 （IPS）细胞。在2020年，我们报告了具有非凡同源性的MI-SPCAS9的发展 定向维修能力。建立在这两个主要工作的基础上，我们在这里建议开发和 优化适用于Cf的体内GETX的新型Mi-SACAS9变体。在AIM 1中，我们将发展 MI-SACAS9-KKH-A，对于校正CF引起CFTR突变特别有用。在目标2中 我们将测试CF的两种GETX策略：（i）适合的大型基因敲击策略 纠正所有CFTR突变； （ii）适用于校正的无捐助者策略 复合杂合CFTR突变。成功完成拟议的第一阶段工作 将为第二阶段树立坚实的基础，我们计划评估 临床前CF动物模型中基于MI-SACAS9-KKH-A的GETX策略。