Abstract 128: Safety And Efficacy Of Pro-efferocytic Nanoparticles To Treat Atherosclerosis In A Porcine Model

Background and Aims: Within the atherosclerotic plaque, the formation of a necrotic core is, in part, a consequence of impaired macrophage efferocytosis in which apoptotic vascular cells upregulate “don’t-eat-me,” anti-phagocytic ligand CD47. In vivo , translational murine model studies demonstrating off-target effects of anti-CD47 antibody-mediated blockade prompted the development and successful validation of a macrophage-specific nanotherapy loaded with a chemical inhibitor of Src homology 2 domain-containing phosphatase-1 (SHP-1), a small molecule downstream of the CD47-SIRPα signaling axis. We aimed to test the safety and efficacy of this SHP-1 inhibitor nanotherapy in preventing atherosclerosis in a pre-clinical porcine model. Methods and Results: Sixteen LDLR -/- pigs were fed an atherogenic diet and treated with single-walled carbon nanotubes (SWNT) loaded with SHP1 inhibitor (SWNT-SHP1i) (n=8) or with SWNT alone (n=8), dosed weekly for three months. Blood samples were collected at baseline and at monthly intervals. The lipid panel, CMP, and CBC demonstrated no significant difference between the SWNT-SHP1i and control treatment groups at each timepoint. Survey of major arterial beds by histology revealed early-stage fatty streak disease within the left and right coronary artery (RCA) ostium in addition to the abdominal aorta distal to the renal arteries. Pigs underwent PET/CT in the final week of treatment. The SWNT-SHP1i treated cohort displayed a reduced carotid artery uptake of 18F-FDG compared to the controls (p = 0.017). Bulk RNA sequencing analysis of the carotid artery demonstrated multiple differentially expressed pathways related to hemostasis and the immune response. Conclusion: In a porcine model, macrophage-specific SWNT-SHP1i treatment is not significantly associated with anemia, thus circumventing off-target effects of global anti-CD47 blockade. PET/CT reveals evidence of significantly decreased vascular inflammation in the carotid arteries in the SWNT-SHP1i treated cohort. Bulk RNA-seq confirms numerous significant differentially expressed genes. Ongoing blinded, quantitative histological analysis will further compare both plaque burden and plaque M1/M2 macrophage content between the two cohorts.