Pre-Clinical Testing Core

项目摘要临床前试验(PTC)核心 成立了IU/JAX/PITT模型的临床前测试核心(PTC)-AD中心作为专家 技术资源，并提供基础设施，以实现严格和公正的临床前筛查 建议的治疗干预措施由更大的研究团体提名，并将在小鼠身上进行测试 以MODEL-AD疾病建模项目为特征的晚发性阿尔茨海默病模型。 PTC流水线包括评估药物稳定性、配方和确认的初始初筛 药效学(PD)和预测性PK/PD建模以 告知长期慢性疗效研究的给药方案。二次筛查包括慢性治疗 利用翻译的非侵入性评估体内靶点参与和疾病修改活动 PET/CT和行为评估，以确定治疗窗口。只要化合物符合 针对这些终端预先确定的通过/不通过标准，相关的认知终端疗效评估 通过脑电、液体和成像生物标志物检测神经生理结果。最后， 在慢性药物治疗结束时，多组学分析(即蛋白质组学、转录组学和 代谢组学)对脑、血液和脑脊液进行检测，以确定响应于 药物治疗。在最初的供资期间，技术合作中心建立了最佳做法，并验证了为 包括小分子和生物制品，并建立了一种机制，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。建立在这些基础上 里程碑，对于模型-AD的下一阶段，提出了以下补充的具体目标 最终目标是为药物反应提供更好的预测性洞察，并改进临床前到临床的转换： 具体目标 目标1：利用严格的PTC测试策略支持对Stop-AD提交的药物进行筛选。 目标2：加强PTC筛查策略以建立对治疗的分子反应特征 干预措施。 目的3：建立新型生物标志物在预测治疗干预效果方面的应用。

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.