Pre-Clinical Testing Core

临床前试验（PTC）核心项目总结 IU/JAX/PITT MODEL-AD中心的临床前测试核心（PTC）成立， 技术资源，并提供基础设施，使严格和公正的临床前筛选， 由更大的研究界提名的拟议治疗干预措施，并将在小鼠中进行测试 由MODEL-AD疾病建模项目表征的晚发性阿尔茨海默病（LOAD）模型。 PTC管道包括初始的初级筛选，用于评估药物稳定性、配方和确认 随后进行药效学（PD）和预测性PK/PD建模， 告知长期慢性疗效研究的剂量方案。二次筛选包括慢性治疗 其利用翻译的非侵入性方法评估体内靶向接合和疾病修饰活性， PET/CT和行为评估，以确定治疗窗口。如果化合物符合 这些终点的预先确定的GO/No-GO标准，对认知终点的疗效评价相关 与通过EEG测量的神经生理学结果相关联，并且进行流体和成像生物标志物。最后， 在慢性药物治疗结束时，多组学分析（即蛋白质组学，转录组学， 进行脑、血液和CSF的代谢组学（代谢组学）以确定响应于 药物治疗在最初的供资期间，技术合作司确定了最佳做法，并验证了以下项目的管道： 小分子和生物制剂，并建立了一个机制，供研究界提名 他们的化合物通过提交到STOP-AD门户网站进行筛选。根据这些 里程碑，对于下一阶段的模型-AD，提出了以下补充具体目标， 最终目标是提供更好的药物反应预测见解，并改善临床前到临床的转化： 具体目标 目标1：利用严格的PTC测试策略支持STOP-AD申请的药物筛选。 目的2：加强PTC筛查策略，以建立治疗药物的分子应答特征 干预。 目的3：建立新的生物标志物的效用，以预测疗效的治疗干预。

PROJECT SUMMARY PRECLINICAL TESTING (PTC) CORE The Preclinical Testing Core (PTC) of the IU/JAX/PITT MODEL-AD Center was established to serve as an expert technical resource and provide the infrastructure to enable rigorous and unbiased preclinical screening of proposed therapeutic interventions nominated by the greater research community, and to be tested in mouse models of late onset Alzheimer’s disease (LOAD) characterized by the MODEL-AD Disease Modeling Project. The PTC pipeline includes an initial primary screen, which evaluates drug stability, formulation, and confirmation of the active pharmaceutical ingredient followed by pharmacodynamics (PD) and predictive PK/PD modeling to inform the dose regimen for long-term chronic efficacy studies. The secondary screen includes chronic treatment that evaluates in vivo target engagement and disease modifying activity utilizing translational non-invasive PET/CT and behavioral assessments to determine a therapeutic window. Provided the compound meets the pre-determined Go/No-GO criteria for these endpoints, evaluation for efficacy on cognitive endpoints correlated to neurophysiological outcomes as measured by EEG, and fluid and imaging biomarkers are conducted. Finally, at the conclusion of chronic drug treatment, multi-omics analysis (i.e. proteomics, transcriptomics, and metabolomics) of brain, blood, and CSF are conducted to determine the molecular signatures in response to drug treatment. In the initial funding period, the PTC established best practices and validated the pipeline for both small molecules and biologics as well as established a mechanism for the research community to nominate their compounds for screening through submission to the STOP-AD portal website. Building on these milestones, for this next phase of MODEL-AD, the following complementary specific aims are proposed with the ultimate goals to provide better predictive insight on drug response and improve preclinical to clinical translation: Specific Aims Aim 1: Support Drug Screening of STOP-AD Submissions Utilizing the Rigorous PTC Testing Strategy. Aim 2: Enhance the PTC Screening Strategy to Establish Molecular Response Signatures to Therapeutic Interventions. Aim 3: To Establish the Utility of Novel Biomarkers to Predict Efficacy of Therapeutic Interventions.