Experimental study
Intramural coronary delivery of advanced antisense oligonucleotides reduces neointimal formation in the porcine stent restenosis model

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Abstract

Objectives

We evaluated the long-term influence of intramural delivery of advanced c-myc neutrally charged antisense oligonucleotides (Resten-NG) on neointimal hyperplasia after stenting in a pig model.

Background

Neointimal hyperplasia after percutaneous coronary interventions is one of the key components of the restenotic process. The c-myc is a critical cell division cycle protein involved in the formation of neointima.

Methods

In short-term experiments, different doses (from 500 μg to 5 mg) of Resten-NG or saline were delivered to the stent implantation site with an infiltrator delivery system (Interventional Technologies, San Diego, California). Animals were euthanized at 2, 6 and 18 h after interventions, and excised vessels were analyzed for c-myc expression by Western blot. In long-term experiments, either saline or a dose of 1, 5 or 10 mg of Resten-NG was delivered in the same fashion, and animals were euthanized at 28 days after the intervention.

Results

Western blot analysis demonstrated inhibition of c-myc expression and was dose dependent. Morphometry showed that the intimal area was 3.88 ± 1.04 mm2in the control. There was statistically significant reduction of intimal areas in the 5 and 10 mg groups (2.01 ± 0.66 and 1.95 ± 0.91, respectively, p < 0.001) but no significant reduction in the 1 mg group (2.81 ± 0.56, p > 0.5) in comparison with control.

Conclusions

This study demonstrated that intramural delivery of advanced c-myc neutrally charged antisense morpholino compound completely inhibits c-myc expression and dramatically reduces neointimal formation in a dose dependent fashion in a porcine coronary stent restenosis model, while allowing for complete vascular healing.

Abbreviations

H&E
hematoxylin and eosin
IBC
Infiltrator Balloon Catheter
PMO
phosphorothioate morpholino oligomers
PTCA
percutaneous transluminal coronary angioplasty
SMC
smooth muscle cell

Cited by (0)

These studies were supported in part by a research grant from the Medical Research Fund at Lenox Hill Hospital (New York, New York), AVI BioPharma (Portland, Oregon) and Cook Cardiology (Broomfield, Colorado).