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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.

本申请中提出的研究将推进3D类器官模型中人体细胞中体细胞基因组编辑的体外安全性和有效性测试。对于基因组编辑，人类类器官有可能成为一种理想的工具，因为治疗靶点是人类基因组，而人类基因组不能在任何其他物种中复制。类器官还具有通量和人类副作用的预测性的优势。然而，重要的是要在这种情况下测试类器官的效用和价值，因为这将被证明是研究新药的一种使能技术。为了实现这一目标，我们将产生一组代表人类肾脏、肝脏、大脑、肺、视网膜和/或心脏的不同类器官，作为基因编辑应用非常感兴趣的重要器官系统。对于我们“盘中的身体”中的每个器官谱系，我们将展示测量编辑率和副作用的测定。将对这些试验进行优化，以建立具有试验稳定性、重现性和分析范围可定量测量的参比标准品。类器官数据集将与使用类似基因编辑技术的合作团队并行工作产生的数据集进行比较。其目的是证明人类类器官培养物中的安全性和有效性测定，并结合其他系统中的补充评估，作为一种易于处理的范例，以支持基因组编辑疗法在人类临床试验中的发展。为了最大限度地发挥影响，我们将专注于在多器官系统中广泛用于各种基因组编辑疗法的检测。来源于人多能干细胞的类器官具有组织的许多关键特征，包括复杂排列的多种细胞类型，并表达与罕见人群相关的特定疾病表型。出于监管考虑，迫切需要确定其保真度和预测能力。在这些研究中，我们将证明人类类器官和其他临床前模型之间的一致性和协同作用。因此，提出的具体目标是通过评估人类类器官中不良事件的剂量依赖性效率来降低治疗性基因组编辑方法的风险。总的来说，这些研究将产生人类类器官中的基因组编辑模型，其结果可以与矫形模型进行比较，以建立可应用于一系列组织和疾病的监管范式。