Utility of Human Organoids for Safety and Efficiency Evaluations of Genome Editing Therapeutics

人类类器官在基因组编辑治疗安全性和效率评估中的应用

基本信息

批准号：
10667181
负责人：
Benjamin Solomon Freedman
金额：
$ 35.17万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667181
关键词：
3-Dimensional APOL1 gene Acceleration Adverse event American Animal Model Animals Architecture Biological Assay Biological Models Brain Cell Culture Techniques Cell Line Cells Clinic Clinical Clinical Trials Collaborations Complement Complex DNA DNA Sequence Data Data Set Disease Dose Elements Ensure Evaluation Genes Heart Human Human Genome Immune response In Vitro Individual Innate Immune Response Intervention Investigation Investigational Drugs Kidney Liver Lung Macaca mulatta Measurement Measures Methodology Microscopy Modeling Monitor Monkeys Neurons Oncogenic Organ Organoids Outcome Patients Phase Population Pre-Clinical Model Predictive Value Primates Protocols documentation Reference Standards Reproducibility Retina Ribonucleoproteins Risk Rodent Route Safety Species Specificity Structure System Technology Testing The Cancer Genome Atlas Therapeutic Tissues Toxicology Viral body system cell type clinical development college commercialization comparative detection assay disease phenotype drug development experimental study genome editing genotoxicity human data human pluripotent stem cell human tissue immunogenic improved in vivo interest meetings nonhuman primate novel nuclease outcome prediction pre-clinical prototype research clinical testing response side effect single cell sequencing somatic cell gene editing synergism therapeutic candidate therapeutic genome editing therapeutic target tool

项目摘要

PROJECT SUMMARY The studies proposed in this application will advance in vitro safety and efficiency testing for somatic cell genome editing in human cells in 3D organoid models. For genome editing, human organoids have the potential to be an ideal tool, as the therapeutic target is the human genome, which cannot be replicated in any other species. Organoids also have advantages for throughput and predictivity of human side effects. It is important, however, to test the utility and value of organoids in this context, for this to be demonstrated as an enabling technology for investigational new drugs. To achieve this, we will produce a set of diverse organoids representing human kidney, liver, brain, lung, retina, and/or heart as vital organ systems of great interest to gene editing applications. For each organ lineage in our 'body in a dish', we will demonstrate assays to measure editing rates as well as side effects. These assays will be optimized to establish reference standards with quantifiable measurements of assay stability, reproducibility, and analytical range. Organoid datasets will be compared with datasets produced in parallel efforts by collaborating teams using similar gene editing technologies. The objective is to demonstrate safety and efficiency assays in human organoid cultures in conjunction with complementary assessments in other systems as a tractable paradigm to support the advancement of genome editing therapeutics to human clinical trials. To maximize impact, we will focus on assays that will be broadly useful for a wide variety of genome editing therapeutics, in multiple organ systems. Organoids derived from human pluripotent stem cells possess many key features of tissues, including diverse cell types in sophisticated arrangements, and express specific disease phenotypes associated with rare populations. For regulatory consideration, there is a critical need to determine their fidelity and prediction capacity. In these studies, we will demonstrate concordance and synergy between human organoids and other preclinical models. Thus, the Specific Aim proposed is to de-risk therapeutic genome editing approaches by assessing dose-dependent efficiency with adverse events in human organoids. Collectively, these studies will produce models of genome editing in human organoids with outcomes that can be compared to orthologous models to establish a regulatory paradigm which can be applied to a range of tissues and diseases.

项目摘要本应用程序中提出的研究将在3D类器官模型中对人类细胞中体细胞基因组编辑进行体外安全和效率测试。对于基因组编辑，人体器官具有成为理想工具的潜力，因为治疗靶标是人类基因组，在任何其他物种中都无法复制。器官在人类副作用的吞吐量和预测性方面也具有优势。但是，重要的是要在这种情况下测试器官的效用和价值，以证明这是一种研究新药的能力。为了实现这一目标，我们将生产一组代表人类肾脏，肝脏，脑，肺，视网膜和/或心脏作为基因编辑应用具有极大兴趣的器官系统的各种器官。对于“盘子中的身体”中的每个器官谱系，我们将演示测量编辑速率和副作用的测定。这些测定将被优化以建立参考标准，并具有可量化的测定稳定性，可重复性和分析范围的测量值。 Organoid Dataset将与使用类似基因编辑技术的团队合作在同行工作中生产的数据集进行比较。目的是证明人体器官培养物中的安全性和效率测定法与其他系统中的互补评估，作为一种可拖动的范式，以支持基因组编辑治疗剂的进步人类临床试验。为了最大程度地发挥影响，我们将专注于在多个器官系统中对各种基因组编辑治疗剂的广泛有用的测定。源自人多能干细胞的器官具有组织的许多关键特征，包括各种细胞类型的复杂排列，并表达与稀有种群相关的特定疾病表型。为了进行监管的考虑，确定其忠诚度和预测能力的迫切需要。在这些研究中，我们将证明人类器官与其他临床前模型之间的一致性和协同作用。因此，提出的具体目的是通过评估人体器官中不良事件的剂量依赖性效率来去风险治疗基因组编辑方法。总的来说，这些研究将在人体器官中产生基因组编辑模型，并将其结果与直系同源模型进行比较，以建立可以应用于一系列组织和疾病的调节范式。