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.

项目摘要临床前鼠标模型核心 小鼠模型是理解疾病机制并作为关键的关键组成部分 新型治疗学临床前测试的平台。尽管体外系统对于筛选A非常有用 大量基因编辑设计，小鼠提供了可拖动的哺乳动物系统，可清楚地证明 使用经过验证的疾病模型在体内功能疗效。这些数据对于支持新的IND至关重要 治疗。临床前小鼠模型核心的结构是提供集中式和缩放模型的访问 体内交付专业知识和表型能力，以支持各个疾病研究项目 该计划旨在我们对基因组编辑治疗剂进行验证的目标。杰克逊 实验室（JAX）包含世界上最大的人类疾病的老鼠模型，包括所有关键 该程序的模型。此外，JAX利用其专业知识和规模来开发广泛的服务 这将有助于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，他们在过去的三年中执行了更多 全球400多名调查员的基于CRISPR/CAS9的2200个基于CRISPR/CAS9的项目， 包括大规模的高通量KOMP2中心，该中心产生了1000多个基因敲除。 JAX还建立了，装备并开设了一个世界一流的老鼠表型诊所，即JAX生物识别中心 分析可满足各个教师项目以及大规模的表型需求。批判性，我们的 拟议的核心将基于我们当前作为当前阶段的小动物测试中心的经验 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，可提供全面的临床前功效，耐受性和药代动力学 使用鼠标模型进行测试。在过去的四年中，我们的测试中心与10个资助的团队合作 提供新型基因组编辑器输送系统的第二站点验证，独立评估其效率 和记者模型中的特异性。临床前鼠标模型核心将充分利用此特殊的优势 基础架构和专业知识，以实现该U19计划的目标。我们提出了这些具体目标：1） 提供关键的动物模型资源来支持各个疾病项目，包括优化模型 和队列产生； 2）执行基于原则实验证明的交付验证研究 对于每个疾病项目。