Preclinical Mouse Model Core

临床前小鼠模型核心

• 批准号: 10668764
• 负责人: Stephen A Murray
• 金额: $ 66.97万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-16 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668764
• 关键词: Animal Model; Animal Testing; Biodistribution; Biological; Biometry; Breeding; CRISPR/Cas technology; Clinic; Collection; Data; Disease; Disease model; Dose; Drug Kinetics; Evaluation; Faculty; Formulation; Funding; Generations; Genes; Genetic Engineering; Genome; Goals; Human Engineering; In Vitro; Individual; Infrastructure; Laboratories; Leadership; Modeling; Molecular; Mus; Outcome; Pharmacodynamics; Pharmacology; Phase; Phenotype; Preclinical Testing; Program Research Project Grants; Rare Diseases; Reporter; Research Personnel; Resources; Services; Site; Specificity; Structure; System; Technology; Testing; The Jackson Laboratory; Time; Tissue Harvesting; Toxicology; Validation; Viral Vector; Work; adeno-associated viral vector; cohort; cost effective; design; experience; experimental study; genome editing; human disease; human model; improved; in vivo; knockout gene; mouse model; nervous system disorder; novel; novel therapeutics; pre-clinical; precision genetics; preclinical efficacy; preclinical study; programs; screening; skills; somatic cell gene editing; therapeutic development; therapeutic genome editing; translational goal; validation studies

PROJECT SUMMARY PRECLINICAL MOUSE MODEL CORE Mouse models are a critical component to both understanding disease mechanisms and to serve as a key platform for preclinical testing of novel therapeutics. Although in vitro systems are very useful for screening a large number of gene editing designs, mice provide a tractable, mammalian system to clearly demonstrate functional efficacy in vivo using a validated model of disease. These data are critical to support an IND for new treatments. The Preclinical Mouse Model Core is structured to provide centralized and scaled access to models, in vivo delivery expertise, and phenotyping capabilities to support the individual disease research projects for this program, towards our goal of IND-enabling validation of genomic editing therapeutics. The Jackson Laboratory (JAX) houses the world's largest collection of mouse models of human disease, including all key models for this program. In addition, JAX has leveraged its expertise and scale to develop a broad set of services that will serve to further support the needs of the individual projects in a cost-effective and high-throughput manner. This includes our Genetic Engineering Technology team who has, over the past 3 years, executed more than 2,200 CRISPR/Cas9-based projects of all levels of complexity for 400+ investigators around the world, including the large-scale, high-throughput KOMP2 Center that has produced more than 1,000 gene knockouts. JAX has also built, outfitted, and opened a world-class mouse phenotyping clinic, the JAX Center for Biometric Analysis, which serves both individual faculty projects as well as larger-scale phenotyping needs. Critically, our proposed Core will build on our current experience as a Small Animal Testing Center for the current Phase of the Somatic Cell Genome Editing consortium. This program leverages the capabilities of the JAX In Vivo Pharmacology Service, which provides comprehensive pre-clinical efficacy, tolerability, and pharmacokinetic testing using mouse models. Over the past four years, our testing center has worked with 10 funded teams to provide second-site validation of novel genome editor delivery systems, independently evaluating their efficiency and specificity in reporter models. The Preclinical Mouse Models Core will take full advantage of this exceptional infrastructure and expertise to achieve the goals of this U19 program. We propose these Specific Aims: 1) To provide key animal model resources to support the individual disease projects, including optimization of models and cohort generation; and 2) To execute delivery validation studies that build on proof-of-principle experiments for each disease project.

项目概要 临床前小鼠模型核心 小鼠模型是理解疾病机制的关键组成部分，也是研究疾病的关键 新疗法的临床前测试平台。尽管体外系统对于筛选 大量的基因编辑设计，小鼠提供了一个易于处理的哺乳动物系统来清楚地展示 使用经过验证的疾病模型进行体内功能功效。这些数据对于支持新药 IND 至关重要 治疗。临床前小鼠模型核心的结构旨在提供对模型的集中和扩展访问， 体内递送专业知识和表型分析能力，以支持个体疾病研究项目 该计划旨在实现基因组编辑疗法的 IND 验证的目标。杰克逊 实验室（JAX）拥有世界上最大的人类疾病小鼠模型收藏，包括所有关键的 该程序的模型。此外，JAX 还利用其专业知识和规模开发了一系列广泛的服务 这将有助于以具有成本效益和高通量的方式进一步支持各个项目的需求 方式。这包括我们的基因工程技术团队，他们在过去 3 年里执行了更多 为全球 400 多名研究人员提供超过 2,200 个基于 CRISPR/Cas9 的各种复杂程度的项目， 其中包括大规模、高通量的 KOMP2 中心，已产生超过 1,000 个基因敲除。 JAX 还建立、装备并开设了世界一流的小鼠表型诊所，即 JAX 生物识别中心 分析，既满足个人教师项目，也满足更大规模的表型分析需求。关键的是，我们的 拟议的核心将建立在我们当前阶段作为小动物测试中心的经验基础上 体细胞基因组编辑联盟。该程序利用了 JAX In Vivo 的功能 药理学服务，提供全面的临床前疗效、耐受性和药代动力学 使用小鼠模型进行测试。四年来，我们的测试中心与10个资助团队合作， 提供新型基因组编辑传递系统的第二位点验证，独立评估其效率 以及记者模型的特异性。临床前小鼠模型核心将充分利用这一特殊优势 基础设施和专业知识来实现​​该 U19 计划的目标。我们提出以下具体目标： 1) 提供关键动物模型资源以支持单个疾病项目，包括模型优化 和队列生成； 2) 执行基于原理验证实验的交付验证研究 对于每个疾病项目。