Federal Grant Award Summary

The National Institute on Aging (Aging Research program, CFDA 93.866) awarded a $1.42 million Project Grant to The Regents of the University of California, San Francisco to develop cell type-specific drug repurposing therapeutics for Alzheimer's Disease. The research leverages single-nucleus transcriptomic profiling (VINE-SEQ) and computational drug repositioning tools to identify and validate repurposed pharmaceutical compounds capable of modulating disease-relevant gene expression signatures across distinct brain cell populations—specifically neurons, glia, and vascular/perivascular cells. Early computational analyses have nominated over 80 potential drug candidates, including letrozole, irinotecan, sirolimus, and vorinostat, which show promise in addressing neuroimmune and vascular dysfunction implicated in Alzheimer's pathogenesis.

The project delivers research outputs through two primary aims spanning the five-year award period (June 1, 2026 through May 31, 2031). Aim 1 validates and optimizes repurposed drugs targeting neuron-glial dysfunction through in vitro testing using induced pluripotent stem cell (iPSC)-derived neurons, glia, and assembloid models, alongside chronic mouse dosing studies in transgenic Alzheimer's models (5XFAD, htau) with multi-omic readouts measuring amyloid burden, neuroinflammation, and synaptic loss. Aim 2 focuses on vascular and perivascular compartment dysfunction. The research employs advanced analytical tools including longitudinal bioluminescent imaging and plasma biomarkers to assess drug efficacy, target engagement, and safety, ultimately generating preclinical evidence to accelerate precision therapeutic development for this complex neurodegenerative disorder.