Abstract 13468: Single-Cell Driven Drug Repositioning Approach Identifies a New Anti-Atherosclerotic Compound Targeting Myeloid Cells

Abstract

Introduction: Inflammation is a key driver of atherosclerosis. The identification of new treatments and strategies targeting the specific inflammatory signaling that persists in optimally treated atherosclerotic patients remain an unmet clinical need. Hypothesis: The integration of time-of-flight mass cytometry (CyTOF), gene expression analysis, and drug repositioning computational approaches applied to pre-clinical validation in models of the disease using non-invasive imaging will help to identify drugs tailored to residual inflammatory signaling in patients with atherosclerosis. Methods: We developed a new systems biology pipeline to identify new therapeutic/indication pair that combines CyTOF and RNA sequencing (RNA-seq) data analysis of clinical samples from patients with carotid and coronary artery disease (CVD) ( Fig. 1A ). This approach allowed the identification of new uses for existing compounds. The predicted anti-atherosclerotic effect was validated in ApoE-/- mice and in a rabbit model of atherosclerosis using 18 F-Fluorodeoxyglucose (FDG) PET-MRI. Results: We found a specific inflammatory signature in CD14 + monocytes stimulated with CVD plasma that was used to identify 50 small molecules predicted to reverse this signature. CyTOF screening of the top eight candidate compounds showed that Saracatinib—a phase 2a-ready Src/Abl inhibitor—blunted the inflammatory response found in CD14 + monocytes ( Fig. 1B ). The anti-atherosclerotic efficacy of Saracatinib was confirmed in ApoE-/- mice fed a high fat diet ( Fig.1C ). In the atherosclerotic rabbit model, Saracatinib reduced plaque inflammation measured as reduction of 18 F-FDG uptake by PET-MRI ( Fig. 1D ). Conclusions: These data support the use of our integrated systems biology pipeline as a powerful approach to identify new immune signature specific to patients with atherosclerosis that can be leveraged to identify new indications for existing drugs to treat cardiovascular disease.