SCGE Comparative Studies Supplement

非人类灵长类动物测试中心支持推进基因组编辑领域的研究， 这些技术在未来用于治疗人类疾病。本报告中提出的研究 补充应用程序将两个互补的SCGE联盟团队聚集在一起， 体细胞基因组编辑的体外和体内安全性和效率测试。体外成分 在3D类器官模型中处理人类细胞，这是一个快速和高通量的临床前测试平台。 评估。然而，类器官可以预测体内反应的程度仍然不清楚，因此， 系统将与协同临床前灵长类动物模型集成，以解决感兴趣的主题， 监管机构，如剂量反应，编辑输送组件，安全性和潜在毒性， 指导临床前/临床监测。作为概念验证的原型，研究集中在肾脏上，因为 约2000万美国人患有慢性肾脏疾病。肾脏疾病正在上升，特别是在儿童中， 一个不成比例地遭受基因原因的人群，这些原因可能是基因组编辑的目标。 提出了由腺相关病毒（AAV）递送的CRISPR/Cas9编辑，以在细胞中引入特异性编辑。 AAVS 1靶基因座。这是一个理想的候选者，因为它在人类和恒河猴中表达， 序列的人类类器官的体外研究将通过利用直接的 超声引导下的肾内入路。总的来说，这些研究将比较人类 肾类器官与非人灵长类动物的结果，以建立一个新的监管模式， 应用于一系列组织和疾病。

The Nonhuman Primate Testing Center supports studies that advance the genome editing field, contributing to the future translation of these technologies for the treatment of human disease. The studies proposed in this supplemental application bring together two complementary SCGE Consortium teams to advance combined in vitro and in vivo safety and efficiency testing for somatic cell genome editing. The in vitro component addresses human cells in a 3D organoid model, a rapid and high-throughput testing platform for preclinical assessments. However, the degree to which organoids can predict responses in vivo remains unclear thus this system will be integrated with the synergistic preclinical primate model to address topics of interest to regulatory agencies such as dose response, editing delivery components, safety, and potential toxicities to guide preclinical/clinical monitoring. As a prototype for proof-of-concept, studies focus on the kidney because ~20 million Americans suffer from chronic kidney disease. Kidney disease is on the rise particularly in children, a population that suffers disproportionately from genetic causes that could be targeted with genome editing. CRISPR/Cas9 editing delivered by adeno-associated virus (AAV) is proposed to introduce specific edits at the AAVS1 target locus. This is an ideal candidate because it is expressed in human and rhesus with conserved sequences. In vitro studies in human organoids will be paralleled with investigations that utilize a direct ultrasound guided intrarenal approach in young monkeys. Collectively, these studies will compare human kidney organoids with outcomes in nonhuman primates to establish a new regulatory paradigm which can be applied to a range of tissues and diseases.