Microphysiological systems to Advance Precision medicine for Alzheimer's Disease and Related Dementias (MAP-AD)

Indiana University Indianapolis, Indianapolis IN

Investigators

Abstract

Project Summary/Abstract Preclinical Efficacy and Safety (PES) Core The Preclinical Efficacy and Safety (PES) Core of the Indiana University Microphysiological systems to Advance Precision medicine (IU MAP-AD) Center will provide an infrastructure for rigorous and reproducible preclinical efficacy and safety testing of therapeutic agents for the treatment Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) pathophysiology in Microphysiological Systems (MPS). Our innovative approach is designed to address the urgent need for more accurate and predictive models in therapeutic discovery and optimization, bridging the gap between animal models and human clinical trials. The PES Core will transfer MPS models from the MPS Models Development and Validation (MMDV) Core. The Core will optimize and standardize these models with therapeutic agents and pharmacodynamic biomarkers. Initially anti- amyloid antibodies that have demonstrated efficacy (Lecanemab) and those that failed (Solanezumab) will serve as positive controls and negative controls respectively. IgG controls and Fc silent versions of these antibodies will be used to dissect the beta amyloid targeting and immunomodulatory effects of these antibodies. Anti- TREM2 agonist antibodies will be used to further explore neuroinflammation and transcytoses through the blood- brain barrier (BBB). Downstream targets within the TREM2 signaling pathway, such as PLCG2, SHIP1, and the Src kinase family will be evaluated with small molecule probes made available by the TREAT-AD Center. The Core will investigate the use of recently established blood-based biomarkers (NfL, GFAP, P-tau217, Abeta 1-42 and Abeta 1-40) and exploratory markers of synaptic degradation (i.e. Neurogranin, SNAP-25), inflammation (sTrem2, SPP1), BBB integrity (VEGF, PDGFRβ and tight junction proteins) and cytotoxicity (LDH). The PES Core will optimize and standardize the MPS models in a rigorous and robust setting with a goal of refining these models to reflect accurately human disease pathophysiology and improve the predictive validity of therapeutic responses for drug optimization. This aim seeks to ensure that the assessment of candidate drugs in these models is both robust and reproducible, leading to more reliable data that can inform clinical trial designs and therapeutic strategies. Another objective of the PES Core is to develop AI-guided, closed-loop, perfusable microfluidic systems. These systems will accurately replicate in vivo pharmacokinetics and pharmacodynamics (PK/PD), offering an advanced platform to measure the effects of therapeutic agents within MPS models under dynamic, physiologically relevant conditions. This approach will reduce reliance on animal models, where species variations often hinder clinical translation. The BCB Core will provide the PES Core with crucial insights into genetic and molecular aspects of AD to guide the selection of additional PD markers for demonstrating the normalization of entire gene regulatory networks. In collaboration with the IU MODEL-AD and TREAT-AD teams, the PES Core will assess the effectiveness of these standardized MPS models in testing novel pharmacological treatments targeting various biological pathways, including neuroinflammation and cerebrovascular health.