Journal article
Smooth Muscle Cell-targeted RNA Aptamer Inhibits Neointimal Formation
Molecular therapy, Vol.24(4), pp.779-787
04/2016
DOI: 10.1038/mt.2015.235
PMCID: PMC4886937
PMID: 26732878
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.
Details
- Title: Subtitle
- Smooth Muscle Cell-targeted RNA Aptamer Inhibits Neointimal Formation
- Creators
- William H Thiel - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USACarla L Esposito - Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, Naples, ItalyDavid D Dickey - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAJustin P Dassie - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAMatthew E Long - Department of Microbiology, University of Washington, Seattle, Washington, USAJoshua Adam - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAJennifer Streeter - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USABrandon Schickling - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAMaysam Takapoo - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAKatie S Flenker - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAJulia Klesney-Tait - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USAVittorio de Franciscis - Istituto di Endocrinologia ed Oncologia Sperimentale, CNR, Naples, ItalyFrancis J Miller Jr - The Veterans Affairs Medical Center, Iowa City, Iowa, USAPaloma H Giangrande - Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.24(4), pp.779-787
- DOI
- 10.1038/mt.2015.235
- PMID
- 26732878
- PMCID
- PMC4886937
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Grant note
- T32HL07344 / NHLBI NIH HHS R01 HL081750 / NHLBI NIH HHS R21 DE019953 / NIDCR NIH HHS T32 HL007344 / NHLBI NIH HHS R21DE019953 / NIDCR NIH HHS I01 BX001729 / BLRD VA R01 CA138503 / NCI NIH HHS R01CA138503 / NCI NIH HHS T32 HL07344 / NHLBI NIH HHS HL081750 / NHLBI NIH HHS P30CA086862 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
- Language
- English
- Date published
- 04/2016
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; Cardiovascular Medicine; Radiation Oncology; Obstetrics and Gynecology; Internal Medicine
- Record Identifier
- 9984094310302771
Metrics
29 Record Views