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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的目标是将基因组编辑器应用于类器官培养物中，以建立一个预测模型，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。本补充申请中提出的研究将两个互补的SCGE联盟团队聚集在一起，以提高体外和体内安全性，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，用于临床前评估的快速高通量测试平台。然而，程度对于哪些类器官可以预测体内反应仍然不清楚，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，例如剂量反应、编辑递送组分、安全性和潜在毒性，以指导临床前/临床监测.作为概念验证的原型，研究重点是肾脏，因为大约2000万美国人患有慢性肾病。肾脏疾病正在上升，特别是在儿童中，不成比例地来自基因组编辑可能针对的遗传原因。CRISPR/Cas9编辑提出了由腺相关病毒（AAV）递送的重组腺病毒载体，以在AAVS1靶基因座处引入特异性编辑。总的来说，这些研究将建立一个新的监管模式，可应用于一系列组织和疾病。