Local MicroRNA Modulation Using a Novel Anti-miR-21–Eluting Stent Effectively Prevents Experimental In-Stent Restenosis

Abstract

Objective Despite advances in stent technology for vascular interventions, in-stent restenosis (ISR) due to myointimal hyperplasia (MH) remains a major complication. Approach and Results We investigated the regulatory role of microRNAs in MH/ISR, utilizing a humanized animal model in which balloon-injured human internal mammary arteries (IMAs) with or without stenting were transplanted into RNU rats, followed by microRNA profiling. miR-21 was the only significantly up-regulated candidate. In addition, miR-21 expression was increased in human tissue samples from patients with ISR compared to coronary artery disease specimen. We systemically repressed miR-21 via intravenous FAM-tagged-LNA-anti-miR-21 (anti-21) in our humanized MH-model. As expected, suppression of vascular miR-21 correlated dose-dependently with reduced luminal obliteration. Further, anti-21 did not impede re-endothelialization. However, systemic anti-miR-21 had substantial off-target effects, lowering miR-21 expression in liver, heart, lung, and kidney with concomitant increased serum creatinine levels. We therefore assessed the feasibility of local miR-21 suppression using anti-21-coated stents. Compared to bare metal stents, anti-21-coated stents effectively reduced ISR, while no significant off-target effects could be observed. Conclusion This is the first study to demonstrate the efficacy of an anti-miR-coated stent for the reduction of ISR.

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions

“…Local delivery of vascular therapeutic miRNA modulators via coated stents has recently been shown to be safe and highly effective. 44 Direct delivery of miR-210 attenuates cardiac injury in mice and has been suggested as a therapeutic agent in ischemic heart disease. 45 Results from our study indicate that not only hypoxia, but also other stimuli, including pathological shear stress and altered blood flow conditions, as well as conditions inducing apoptosis and dedifferentiation, can lead to miR-210 repression in the vasculature, resulting in a downstream induction of proapoptotic mechanisms mainly in SMCs.…”

microRNAs in cardiovascular disease – clinical application

“…Also, a knock-down of miR-21 and miR-221 may reduce neointima formation after vessel injury [150]. Systemically administered antagomiRs and miRmimics have been the method of choice to explore their effect, but had substantial off-target effects and were primarily targeting the kidney, liver, lung and spleen with considerable side effects [150,151]. Therefore, the local administration of miRNAs as therapeutic agents in the prevention of ISR was evaluated [151].…”

“…Systemically administered antagomiRs and miRmimics have been the method of choice to explore their effect, but had substantial off-target effects and were primarily targeting the kidney, liver, lung and spleen with considerable side effects [150,151]. Therefore, the local administration of miRNAs as therapeutic agents in the prevention of ISR was evaluated [151]. The authors successfully implanted antimiR-21 coated vascular stents into human left internal mammarian arteries, grafted those arteries into mice in abdominal aortal position and found a significantly reduced myointima formation compared with a control group treated with bare metal stents (BMS) [151].…”

“…Therefore, the local administration of miRNAs as therapeutic agents in the prevention of ISR was evaluated [151]. The authors successfully implanted antimiR-21 coated vascular stents into human left internal mammarian arteries, grafted those arteries into mice in abdominal aortal position and found a significantly reduced myointima formation compared with a control group treated with bare metal stents (BMS) [151]. This example summarizes the molecular usefulness of miRNA therapeutics as well as the need for and applicability of a sophisticated mode of application to minimize systemic undesirable effects.…”

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

“…Using this approach, Wang et al used an anti-21-coated stent to reduce ISR. 133 Alternative strategies for targeted delivery include conjugation to targeting molecules, such as antibodies, peptides, or other molecules, that allow achievement of site-specific delivery despite systemic administration. Using a different approach, Santulli et al, for example, showed that binding of endogenous miR-126-3p to the Ad-p27-126TS might prevent p27 overexpression in ECs but not in VSMCs.…”