Smooth Muscle Cell–targeted RNA Aptamer Inhibits Neointimal Formation

Abstract

Inhibition of vascular smooth muscle cell (VSMC) proliferation by drug eluting stents has markedly reduced intimal hyperplasia and subsequent in-stent restenosis. However, the effects of antiproliferative drugs on endothelial cells (EC) contribute to delayed re-endothelialization and late stent thrombosis. Cell-targeted therapies to inhibit VSMC remodeling while maintaining EC health are necessary to allow vascular healing while preventing restenosis. We describe an RNA aptamer (Apt 14) that functions as a smart drug by preferentially targeting VSMCs as compared to ECs and other myocytes. Furthermore, Apt 14 inhibits phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) and VSMC migration in response to multiple agonists by a mechanism that involves inhibition of platelet-derived growth factor receptor (PDGFR)-β phosphorylation. In a murine model of carotid injury, treatment of vessels with Apt 14 reduces neointimal formation to levels similar to those observed with paclitaxel. Importantly, we confirm that Apt 14 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. We describe a VSMC-targeted RNA aptamer that blocks cell migration and inhibits intimal formation. These findings provide the foundation for the translation of cell-targeted RNA therapeutics to vascular disease.

Aptamers as targeted therapeutics: current potential and challenges

“…Such disease is generally treated with anti-proliferative/anti-migratory drugs (e.g., paclitaxel) to directly block VSMC activation 110 . Through a cell-based HT-SELEX strategy, a nuclease-resistant RNA aptamer was identified to preferentially target VSMCs over endothelial cells and nonvascular myocytes, and specifically inhibited VSMC migration 111 . In preclinical assessment, this aptamer exhibited a half-life of ~300 h in human serum and no pathological immune response in human peripheral blood mononuclear cells.…”

“…So far, there are many examples of radiolabeled aptamers for nuclear imaging and therapy. The most popularly used radionuclides include 99m Tc, 64 Cu, 68 Ga, and 111 In. An initial example of an aptamer-radionuclide conjugate is a RNA aptamer targeting human tenascin-C (TN-C), a large hexametric glycoprotein that is overexpressed in tumor stroma.…”

Peptidomimetic Targeting of Ca v β2 Overcomes Dysregulation of the L-Type Calcium Channel Density and Recovers Cardiac Function

“…Another issue is the broad tissue distribution of Ca v β2, necessitating careful re-evaluation of the nature and type of carrier to use because the current R7W carrier is not specific to the heart and thus may also have potential effects at other locations such as the vasculature or the sympathetic nervous system. In this regard, the recent development of novel drug carriers (ie, cell-specific aptamers 49 or functionalized nanoparticles 50 ) might allow specific delivery to the heart and thus minimization of short-or long-term secondary side effects. …”

An anti-PDGFRβ aptamer for selective delivery of small therapeutic peptide to cardiac cells

“…Using Gint4.T, we provide the proof-of-concept that the approach is effective and might be exploited within the context of the growing number of therapeutic peptides. However, due to the binding of Gint4.T to the PDGFRβ cell-surface receptor, which in addition to cardiomyocytes is expressed also in other cell types, such as smooth muscle cells and fibroblasts [ 28 – 30 ], further studies are required to identify internalizing aptamers with higher selectivity for the heart.…”