Cell type specific drug repurposing for alzheimer's disease

The National Institute on Aging awarded The Regents of the University of California, San Francisco $1,419,145 on June 1, 2026, under the Aging Research program (CFDA 93.866) to conduct cell-type-specific drug repurposing for Alzheimer's disease using single-nucleus transcriptomic profiling and computational drug repositioning.

The project employs state-of-the-art single-nucleus transcriptomic analysis (VINE-SEQ) and integrative computational tools including Connectivity Map and LINCS to identify compounds capable of modulating disease-relevant gene expression signatures across distinct brain cell types—neurons, glia, and vascular/perivascular cells. Preliminary work has nominated over 80 repurposed drug candidates, including letrozole, irinotecan, sirolimus, and vorinostat, with several demonstrating multi-compartment activity and preclinical promise. The research validates and optimizes these compounds through in vitro studies using induced pluripotent stem cell–derived neurons, glia, and assembloid models, and in vivo validation in mouse models of Alzheimer's disease using longitudinal bioluminescent imaging and plasma biomarkers to assess efficacy, target engagement, and safety. Aim 1 integrates computational predictions with functional co-culture studies, chronic mouse dosing models (including 5XFAD and HTAU lines), and multi-omic readouts of parenchymal pathology including amyloid burden, neuroinflammation, and synaptic loss.

The award period runs from June 1, 2026, through May 31, 2031, with work performed in San Francisco, California. The assistance type is a Project Grant.

Abstract

This proposal presents an innovative and interdisciplinary approach to accelerate the development of effective, precision therapeutics for alzheimer's disease (ad), a complex and heterogeneous neurodegenerative disorder with limited treatment options. Recognizing the critical role of neuroimmune and vascular dysfunction in ad pathogenesis-particularly within the perivascular spaces, the we will leverage state-of-the-art single-nucleus transcriptomic profiling (VINE-SEQ) and integrative computational drug repositioning to identify and test repurposed compounds capable of modulating disease-relevant gene expression signatures at the cell type level. The project builds on extensive preliminary data identifying key ad-related transcriptional signatures across neurons, glia, and vascular/perivascular cells, revealing both known and novel therapeutic targets. Using publicly available and lab-generated transcriptomic datasets, the team employs tools like connectivity map and lincs to predict drug candidates that reverse pathogenic gene networks in distinct brain cell types. Early analyses have already nominated over 80 potential compounds, including letrozole, irinotecan, sirolimus, and vorinostat, several of which show multi-compartment activity and strong preclinical promise. These candidates will be rigorously validated in vitro using ipsc-derived neurons, glia, and assembloid models, and in vivo using mouse models of ad with tools like longitudinal bioluminescent imaging and plasma biomarkers to assess efficacy, target engagement, and safety. Aim 1 seeks to validate and optimize repurposed drugs targeting neuron-glial dysfunction by integrating computational predictions with functional studies in CO-culture systems, chronic mouse dosing models (e.g., 5XFAD, htau), and multi-omic readouts of parenchymal pathology, including amyloid burden, neuroinflammation, and synaptic loss. Aim 2 focuses on the vascular-perivascular axis of ad by using single-cell signatures from VINE-SEQ to identify and test compounds that reverse vascular dysfunction and immune dysregulation in CAA-associated ad models (e.g., TGAPP23), with endpoints including cerebral amyloid angiopathy, blood-brain barrier integrity, and perivascular inflammation. Together, these complementary aims form a robust platform to evaluate and prioritize SEX- and cell-type-specific therapies that address both neuronal and vascular drivers of ad. The collaboration brings together a world-class team with expertise in ad genomics, drug repurposing, systems immunology, mouse modeling, and human cell-based models. By uniting cutting-edge transcriptomic technologies with in vivo pharmacology and a precision medicine framework, this work has the potential to deliver impactful therapeutic strategies that can be rapidly translated into clinical trials for patients with alzheimer's disease.