Abstract 4364300: The Senolytic Navitoclax (ABT263) Reduces Coronary Atherosclerosis and Upregulates Plaque Stability in Atherosclerotic Pigs

Abstract

Background: Cell senescence is an irreversible cell proliferation arrest associated with aging, tumorigenesis, and atherogenesis. The senolytic Navitoclax (ABT263) is an FDA-approved drug for testing in Phase I-III cancer clinical trials. ABT263 induces clearance of senescent cells in vitro and in vivo. Hypothesis: It is unknown whether depletion of senescent cells is sufficient to inhibit atherogenesis. We hypothesized that clearance of senescent cells using ABT263 would reduce the atherosclerotic burden in a pre-clinical model of atherosclerosis, pigs with familial hypercholesterolemia (FH pigs). Methods: ABT263 (or mock, control) was administered to FH pigs fed with pre-existing atherosclerosis (N=5/group). The protocol for ABT263 administration mimicked the drug regimen used for patients. The coronary plaque volume was assessed in vivo by intravascular ultrasound at time zero and at sacrifice, after 3 months of ABT263 administration. Plaque cross-sectional area (CSA) and composition were assessed with Trichrome-stained sections. Results: ABT263 was detected in plasma only in FH pigs in the ABT group (liquid chromatography-mass spectrometry, 226.4±43.4 ng/ml). As reported ABT263 may induce mild thrombocytopenia and neutropenia in patients. We found no significant changes in platelet and neutrophil counts in ABT-treated vs. mock pigs. Senolytic administration did not change levels of circulating immune cells (spectral flow cytometry), including B cells, natural killer cells, and subtypes of T cells and monocytes. Plaque volume was increased by 3.0-fold in the right coronary artery (RCA) and by 3.6-fold in the left anterior descending artery (LAD) in the mock group and by 2.1-fold and by 2.8-fold in ABT-treated pigs (RCA and LAD, respectively) suggesting that ABT263 inhibited plaque progression. ABT263 reduced plaque CSA in RCA (40±6% decrease compared to control, P<0.05) and in LAD (23±4% decrease, P<0.05). Senolytic administration decreased plaque necrotic core area (P<0.05 vs. control) and increased fibrous cap thickness suggesting upregulated features of plaque stability. Conclusions: We tested the effect of Navitoclax (ABT263) on progression of coronary atherosclerosis in FH pigs. ABT263 inhibited the time-dependent increase in atherosclerotic burden and promoted features of a stable plaque phenotype. The results of this trial provide critical experimental background for testing senolytics as innovative anti-atherogenic drugs.