SCGE Comparative Studies Supplement

SCGE 比较研究增刊

基本信息

批准号：
10448959
负责人：
Benjamin Solomon Freedman
金额：
$ 15.83万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448959
关键词：
3-Dimensional AIDS-Associated Nephropathy Acute Acute Disease Acute Renal Failure with Renal Papillary Necrosis Address Adverse effects Adverse event American Antigen Presentation Architecture Autoimmune Diseases Biological Assay CRISPR/Cas technology Cell Line Cells Child Chronic Chronic Disease Chronic Kidney Failure Clinical Clinical Trials Comparative Study Computer Models DNA Damage DNA Sequence Dependovirus Disease Distal Dose Early Diagnosis Endothelial Cells Epithelial Cells Event Experimental Models Fibrosis Frequencies Genes Genetic Genetic Diseases Genome Goals Human Human Genome Immune Impairment In Vitro Inflammation Inflammatory Injury Injury to Kidney Intervention Kidney Kidney Diseases Knowledge Lead Life Lupus Nephritis Malignant Neoplasms Mediating Metabolism Methods Modeling Modification Monitor Mutation Myocardial Infarction Nephritis Nephrons Oncogenic Organ Organoids Outcome Phenotype Physiological Pluripotent Stem Cells Population Pre-Clinical Model Production Proliferating Renal carcinoma Research Risk Rodent Model Safety Structure Syndrome System Testing Therapeutic Time Tissue Model Tissue Sample Tissues Toxic effect Tubular formation Work adaptive immune response carcinogenesis cell type clinical application clinical effect cytokine genome editing high throughput screening human tissue immunogenic in vivo innovation interest kidney cell podocyte pre-clinical pre-clinical assessment preconditioning predicting response predictive modeling prototype replication stress response side effect somatic cell gene editing specific biomarkers therapeutic genome editing tumorigenesis

项目摘要

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.

U01 的目标是在类器官培养中应用基因组编辑器，建立不良反应的预测模型。人类肾细胞类型中的事件，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。本补充申请中提出的研究汇集两个互补的 SCGE 联盟团队，以促进体外和体内联合安全性和体细胞基因组编辑的效率测试。体外组件在我们的 3D 中处理人类细胞类器官模型，一种用于临床前评估的快速高通量测试平台。然而，学位哪些类器官可以预测体内反应仍不清楚，因此该系统将与 SCGE 测试中心的协同研究旨在解决监管机构感兴趣的主题，例如剂量反应、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，研究重点关注肾脏，因为约 2000 万美国人患有慢性肾脏疾病。肾脏疾病的发病率呈上升趋势，尤其是儿童，这是一个深受其苦的人群不成比例地来自可以通过基因组编辑来靶向的遗传原因。 CRISPR/Cas9 编辑提议由腺相关病毒 (AAV) 传递，以在 AAVS1 目标位点引入特定编辑。总的来说，这些研究将建立一个新的监管范式，可应用于一系列组织和疾病。