SCGE Comparative Studies Supplement

U01的目标是将基因组编辑应用于有机物培养，以建立一个预测不良反应的模型。 人类肾脏细胞类型的事件，包括具有危及生命后果的急性和慢性疾病。 基因组编辑平台使得能够有效地操纵人类基因组中的特定DNA序列， 因此具有巨大的治疗潜力。在本补充申请中提出的研究 联合两个互补的SCGE联盟团队，共同推进体外和体内联合安全性和 体细胞基因组编辑效率测试。体外组件在我们的3D中处理人类细胞 有机物模型，用于临床前评估的快速高通量测试平台。然而，学位 目前尚不清楚哪些有机化合物可以预测体内的反应，因此该系统将与 SCGE测试中心的协同研究，以解决监管机构感兴趣的主题，如 剂量反应、编辑递送成分、安全性和潜在毒性以指导临床前/临床 监控。作为概念验证的原型，研究重点放在肾脏上，因为大约2000万美国人 患有慢性肾脏疾病。肾脏疾病正在增加，特别是在儿童中，这是一个遭受痛苦的人群 不成比例的遗传原因可能是基因组编辑的目标。CRISPR/CAS9编辑 由腺相关病毒(AAV)递送的目的是在AAVS1靶点引入特定的编辑。 总的来说，这些研究将建立一种新的调节范式，可以应用于一系列组织 和疾病。

The goal of the U01 is to apply genome editors in organoid cultures to establish a predictive model for adverse events in human kidney cell types, including both acute and chronic disorders with life-threatening consequences. Genome editing platforms enable the efficient manipulation of specific DNA sequences in the human genome, and therefore have enormous potential as therapeutics. 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 our 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 studies in the SCGE Testing Center 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. Collectively, these studies will establish a new regulatory paradigm which can be applied to a range of tissues and diseases.