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.

非人类灵长类动物测试中心支持推进基因组编辑领域的研究，有助于这些技术用于治疗人类疾病的未来翻译。提出的研究补充申请汇集了两个互补的SCGE财团团队，以提高合并体外和体内安全性和效率测试用于体细胞基因组编辑。体外成分在3D类器官模型中解决人类细胞，这是临床前的快速和高通量测试平台评估。但是，器官可以预测体内反应的程度尚不清楚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，例如剂量反应，编辑递送组件，安全性和潜在毒性指南临床前/临床监测。作为概念证明的原型，研究重点是肾脏，因为〜2000万美国人患有慢性肾脏疾病。肾脏疾病尤其是在儿童中，遭受基因组编辑可能针对的遗传原因不成比例的人群。提出了由腺相关病毒（AAV）提供的CRISPR/CAS9编辑，以在 AAVS1目标基因座。这是一个理想的候选人，因为它在人类和恒河猴中表达序列。在人类器官中的体外研究将与使用直接的研究相似超声引导的年轻猴子室内方法。总的来说，这些研究将比较人类在非人类灵长类动物中具有结果的肾脏器官，以建立一个可以是新的调节范式应用于一系列组织和疾病。