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:
  • 金额:
    $ 35.17万
  • 依托单位:
  • 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

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 本申请中提出的研究将推进 3D 类器官模型中人体细胞体细胞基因组编辑的体外安全性和效率测试。对于基因组编辑来说,人类类器官有可能成为理想的工具,因为治疗目标是人类基因组,而人类基因组无法在任何其他物种中复制。类器官在通量和人类副作用的预测性方面也具有优势。然而,重要的是,在这种情况下测试类器官的效用和价值,以便将其证明为研究新药的一项使能技术。为了实现这一目标,我们将生产一组代表人类肾脏、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“培养皿中的身体”中的每个器官谱系,我们将演示测量编辑率和副作用的测定法。这些测定将被优化,以建立参考标准,并可量化测定稳定性、重现性和分析范围。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产生的数据集进行比较。目的是证明人类类器官培养物中的安全性和效率测定与其他系统中的补充评估相结合,作为一种易于处理的范例,以支持基因组编辑疗法向人类临床试验的进展。为了最大限度地发挥影响,我们将重点关注对多个器官系统中的各种基因组编辑疗法广泛有用的检测方法。源自人类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,并表达与稀有群体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,提出的具体目标是通过评估人类类器官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的基因组编辑模型,其结果可以与直系同源模型进行比较,以建立可应用于一系列组织和疾病的监管范式。

项目成果

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Benjamin Solomon Freedman其他文献

Benjamin Solomon Freedman的其他文献

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{{ truncateString('Benjamin Solomon Freedman', 18)}}的其他基金

SCGE Comparative Studies Supplement
SCGE 比较研究增刊
  • 批准号:
    10448959
  • 财政年份:
    2021
  • 资助金额:
    $ 35.17万
  • 项目类别:
Improving the Safety of Genome Editing With Human Kidney Organoids
提高人肾类器官基因组编辑的安全性
  • 批准号:
    10335116
  • 财政年份:
    2019
  • 资助金额:
    $ 35.17万
  • 项目类别:
Improving the Safety of Genome Editing With Human Kidney Organoids
提高人肾类器官基因组编辑的安全性
  • 批准号:
    9810503
  • 财政年份:
    2019
  • 资助金额:
    $ 35.17万
  • 项目类别:
Improving the Safety of Genome Editing With Human Kidney Organoids
提高人肾类器官基因组编辑的安全性
  • 批准号:
    10407081
  • 财政年份:
    2019
  • 资助金额:
    $ 35.17万
  • 项目类别:
Improving the Safety of Genome Editing With Human Kidney Organoids
提高人肾类器官基因组编辑的安全性
  • 批准号:
    10019368
  • 财政年份:
    2019
  • 资助金额:
    $ 35.17万
  • 项目类别:
A Human Organoid Model of Polycystic Kidney Disease
多囊肾病的人体类器官模型
  • 批准号:
    10447043
  • 财政年份:
    2018
  • 资助金额:
    $ 35.17万
  • 项目类别:
A Human Organoid Model of Polycystic Kidney Disease
多囊肾病的人体类器官模型
  • 批准号:
    10190922
  • 财政年份:
    2018
  • 资助金额:
    $ 35.17万
  • 项目类别:
Modeling Polycystic Kidney Disease Using Human Induced Pluripotent Stem Cells
使用人类诱导多能干细胞模拟多囊肾病
  • 批准号:
    8754901
  • 财政年份:
    2014
  • 资助金额:
    $ 35.17万
  • 项目类别:
Modeling Polycystic Kidney Disease Using Human Induced Pluripotent Stem Cells
使用人类诱导多能干细胞模拟多囊肾病
  • 批准号:
    8440919
  • 财政年份:
    2011
  • 资助金额:
    $ 35.17万
  • 项目类别:
Modeling Polycystic Kidney Disease Using Human Induced Pluripotent Stem Cells
使用人类诱导多能干细胞模拟多囊肾病
  • 批准号:
    8534862
  • 财政年份:
    2011
  • 资助金额:
    $ 35.17万
  • 项目类别:

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Multi-Omics for Chronic Kidney Disease
慢性肾脏病的多组学
  • 批准号:
    10744557
  • 财政年份:
    2023
  • 资助金额:
    $ 35.17万
  • 项目类别:
Clonal hematopoiesis and inherited genetic variation in sickle cell disease
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使用 BAC 转基因小鼠模拟 APOL1 高危活体供体的进行性慢性肾病的机制
  • 批准号:
    10726804
  • 财政年份:
    2023
  • 资助金额:
    $ 35.17万
  • 项目类别:
Impact of Clonal Hematopoiesis on the Progression of Kidney Disease
克隆造血对肾脏疾病进展的影响
  • 批准号:
    10611485
  • 财政年份:
    2022
  • 资助金额:
    $ 35.17万
  • 项目类别:
13/14 APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) Clinical Center
13/14 APOL1长期肾移植结果网络(APOLLO)临床中心
  • 批准号:
    10728380
  • 财政年份:
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