title: 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.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Thiel
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, Naples, Italy.
authors.forename: Carla L
authors.initials: CL
authors.lastname: Esposito
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Dickey
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Dassie
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Long
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Adam
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Streeter
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Brandon
authors.initials: B
authors.lastname: Schickling
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Maysam
authors.initials: M
authors.lastname: Takapoo
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Katie S
authors.initials: KS
authors.lastname: Flenker
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Klesney-Tait
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, Naples, Italy.
authors.forename: Vittorio de
authors.initials: Vd
authors.lastname: Franciscis
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.|The Veterans Affairs Medical Center, Iowa City, Iowa, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Miller
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
authors.forename: Paloma H
authors.initials: PH
authors.lastname: Giangrande
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D058426:Neointima / Q000378:metabolism / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats
chemical_list: D052157:Aptamers, Nucleotide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt