Pre-Clinical Testing Core

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.