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SCGE Comparative Studies Supplement

SCGE 比较研究增刊

基本信息

批准号：
10445645
负责人：
DENNIS J. HARTIGAN-O'CONNOR
金额：
$ 32.79万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10445645
关键词：
3-Dimensional Address American Animal Model Animal Testing Animals Benchmarking Biological Assay CRISPR/Cas technology California Callithrix Cells Center for Translational Science Activities Child Chronic Kidney Failure Clinical Clinical Sciences Collaborations Communication Communities Comparative Study Conserved Sequence Dependovirus Development Disease Dose Ensure Evaluation Feedback Fostering Funding Future Genetic Genome Goals Governing Board Human In Vitro Inflammation Infrastructure Investigation Kidney Kidney Diseases Leadership Macaca mulatta Methodology Modeling Monitor Monkeys Office of Administrative Management Organoids Outcome Population Positioning Attribute Primates Procedures Process Publications Reagent Reporter Research Research Personnel Resources Rhesus Safety Schedule Scientist Specificity System Technology Testing Tissues Toxic effect Translations Ultrasonography United States National Institutes of Health Universities Work base data exchange experience genome editing home test human disease immunogenicity in vivo innovation interest meetings member multidisciplinary nonhuman primate organizational structure pre-clinical pre-clinical assessment predicting response programs prototype response somatic cell gene editing synergism tool working group

项目摘要

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.

非人灵长类测试中心支持推进基因组编辑领域的研究，为这些技术用于治疗人类疾病的未来转化。在这篇文章中提出的研究补充性申请将两个互补的SCGE联盟团队聚集在一起，共同推进体细胞基因组编辑的体内外安全性和有效性测试。体外成分在3D有机模型中处理人类细胞，这是一种快速、高通量的临床前测试平台评估。然而，有机化合物能够在多大程度上预测体内的反应仍不清楚，因此系统将与协同的临床前灵长类模型集成，以解决感兴趣的主题监管机构，如剂量反应、编辑递送组件、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，研究重点放在肾脏上，因为约有2000万美国人患有慢性肾脏疾病。肾脏疾病呈上升趋势，尤其是在儿童中。患有不成比例的遗传原因的人群可能会成为基因组编辑的目标。建议在腺相关病毒(AAV)提供的CRISPR/Cas9编辑中引入特定编辑 AAVS1靶基因座。这是一个理想的候选基因，因为它在人类和恒河猴中表达，具有保守性序列。人体类有机化合物的体外研究将与利用直接超声引导下的幼猴肾内入路。总的来说，这些研究将比较人类肾脏有机化合物在非人类灵长类动物中的结果建立一种新的调节范式，可以适用于一系列组织和疾病。