Merck

Smooth Muscle Cell-targeted RNA Aptamer Inhibits Neointimal Formation.

Molecular therapy : the journal of the American Society of Gene Therapy (2016-01-07)
William H Thiel, Carla L Esposito, David D Dickey, Justin P Dassie, Matthew E Long, Joshua Adam, Jennifer Streeter, Brandon Schickling, Maysam Takapoo, Katie S Flenker, Julia Klesney-Tait, Vittorio de Franciscis, Francis J Miller, Paloma H Giangrande
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
PDGF-BB from mouse, recombinant, expressed in E. coli, ≥98% (SDS-PAGE), ≥98% (HPLC), suitable for cell culture
Sigma-Aldrich
Heparin sodium salt from porcine intestinal mucosa, ≥180 USP units/mg