61. Vascular Smooth Muscle Cell RNA Aptamers for the Treatment of Cardiovascular Disease

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality in many countries. Many vascular disorders, including in-stent restenosis, arteriosclerosis, vein graft disease, and cardiac allograft arteriopathy are caused by pathological vascular smooth muscle cell (VSMC) remodeling following injury. An ideal therapeutic intervention would target the VSMCs without impairing the injured vessel re-endothelialization. However, current therapies do not selectively prevent pathological VSMC remodeling leading to impaired re-endothelization, late stent thrombosis and death. Thus, there is a clear need for cell-targeted treatment and prevention options of pathological VSMC remodeling.Our group has described the development of VSMC-specific, aptamers for (1) modulating signaling pathways associated with pathological VSMC remodeling and (2) delivering therapeutic molecules to these cells in vivo. Here we demonstrate that one of these aptamers, Vapt14, inhibits protein kinase B (PKB)/Akt activation and VSMC migration in response to multiple agonists by a mechanism that involves inhibition of platelet-derived growth factor receptor (PDGFR)-beta phosphorylation. In a murine model of carotid injury, treatment of vessels with Vapt14 reduces intimal:medial thickness to levels comparable to that of paclitaxel. Importantly, we confirm that Vapt14 cross-reacts with rodent and human VSMCs, exhibits a half-life of ~300 hours in human serum, and does not elicit immune activation of human peripheral blood mononuclear cells (PBMCs) in vitro. In addition, we confirm delivery of Vapt14 to VSMC in vitro and in vivo with fluorescence microscopy. Studies are being expanded to evaluate aptamer-mediated delivery of therapeutic biomolecules (e.g. small molecules, RNAi modulators) to areas of vascular injury. In summary this work provides an essential foundation for the translation of cell-targeted RNA therapeutics to multiple hyperplastic vascular diseases.