Abstract 11342: Local MicroRNA Modulation is Feasible: A Novel Anti-Mir-21-Eluting Stent Prevents In-Stent Restenosis
Introduction: Despite enormous advances in stent technology for coronary artery interventions, the major limitation of these procedures remains the occurrence of in-stent restenosis (ISR) due to myointimal hyperplasia (MH). The central role of microRNAs (miRNAs) in molecular pathophysiology of MH in cardiovascular diseases may offer attractive concepts for possible therapeutic interventions. However, since systemic miRNA modulation is feared to cause substantial off-target effects, this would hamper its clinical use. For the first time, we herein report on the feasibility of local miRNA modulation using stent coating.
Methods and Results: A humanized animal model for MH/ISR was utilized. Briefly, balloon-injured IMAs with or without stent were implanted into the abdominal aortic position of RNU-rats for 28 days. miRNA profiling in both the human samples and our humanized experimental model showed down-regulation of 7 miRNAs in vessels with MH/ISR, whereas only miR-21 was upregulated.
Initially, therapeutic miR-21 down-regulation was attempted using intravenous application of FAM-tagged-LNA-anti-miRNA-21 (anti-miRNA-21) in our humanized MH-model utilizing non-stented IMAs. Both vascular miRNA-21 expression and luminal obliteration were dose-dependently reduced. miRNA-21 expression in liver, heart, lung and kidney were also significantly reduced, while serum creatinine was increased. Systemic anti-miRNA-21, however, did not impede vessel re-endothelialization.
Successful stent coating with anti-miRNA-21 was confirmed by FAM fluorescence and electron microscopy. In our humanized ISR-model, IMAs carrying anti-miRNA-21-coated stents were compared to IMAs with equivalent bare metal stents. Local delivery of anti-miRNA-21 effectively reduced ISR. Luminal obliteration in anti-miR-21-eluting stents was significantly less than in bare metal stents. We did not observe off-target effects with local anti-miRNA-21 delivery.
Conclusion: This is the first study to demonstrate the efficacy of a drug-eluted stent utilizing miRNA antisense in cardiovascular disease in general, and reduction of ISR with anti-21 in particular.
Author Disclosures: D. Wang: None. T. Deuse: None. M. Stubbendorff: None. E. Chernogubova: None. R.G. Erben: None. S.M. Eken: None. H. Jin: None. M.W. Bergmann: None. B. Behnisch: Employment; Significant; Employee at Translumina. H. Reichenspurner: None. R.C. Robbins: None. P.S. Tsao: None. L. Maegdefessel: None. S. Schrepfer: None.
- © 2014 by American Heart Association, Inc.