Abstract 15519: Site- and Cell-Selective Treatment of Atherosclerosis Using a Combination of RNA Therapeutic Approaches

Abstract

Atherosclerotic plaque formation in the arteries underlies acute coronary syndromes (ACS); therapies to treat atherosclerosis that are both site- and cell-selective are not available. The CANTOS clinical trial demonstrated the benefits of targeting inflammation to reduce adverse cardiac events, but the systemic immune suppression increased incidence of sepsis or death caused by infections, highlighting the need for local inflammation inhibition. To assess the local chronic inflammatory state associated with atherosclerotic plaques, coronary arteries were isolated from non-transplantable human hearts ( Fig. A) from donors ranging in age from 6-months to 72 years old. Donors aged 51-72 had various conditions including hypertension, hypercholesterolemia, and atherosclerosis. Strikingly, qPCR analysis showed an increase in interleukin 1 beta (IL-1β) mRNA levels corresponding to increasing age of the donor and presence of CVD risk factors, with almost a 20-fold increase in the 72 compared to the 6-month-old donor ( Fig. B ).To specifically target the atherosclerotic plaques and the plaque forming cells without affecting the endothelium, we used a cell-penetrating peptide (p5RHH) ( Fig. C ) that self-assembles with synthetic mRNA to form nanoparticles that exclusively target denuded regions of endothelium and atherosclerotic plaques ( Fig. D ). We will deliver small interfering RNA specific to IL-1β and a microRNA switch that consists of synthetic mRNA encoding a cell-cycle inhibitor, p27, that includes a single target site for the endothelial cell specific miR-126, which we previously showed to selectively inhibit intimal hyperplasia and infiltrating immune cells while sparing the vascular endothelium ( Fig. E ). This innovative combination of multiple RNA therapeutics into a single nanoparticle will advance the field of site- and cell-selective anti-atherosclerotic therapy.