The Role of ex-vivo Gene Therapy of Vein Grafts with Egr-1 Decoy in the Suppression of Intimal Hyperplasia

AbstractObjectivesTo test the hypothesis that vein graft intimal hyperplasia can be significantly suppressed by a single intra-operative transfection of the graft with a decoy oligonucleotide (ODN) binding the transcription factor Egr-1.DesignExperimental study.Materials and methodsJugular vein to carotid artery interposition grafts in rabbits were treated with Egr-1 decoy, mutant decoy ODN, vehicle alone, using a non-distending pressure of 300mmHg for 20min, or were left untreated. All animals were fed a 2% cholesterol diet. The animals were sacrificed after 48h, 6 weeks and 12 weeks. Paraffin-embedded vein sections were subjected to angiometric analysis.ResultsSuccessful delivery of the ODN was confirmed by DAPI staining. Quantitative real-time PCR revealed a 60% decrease of the Egr-1 gene expression in the animals in which the Egr-1 decoy ODN was delivered. Cellular proliferation was also significantly decreased as indicated by the Ki-67 labelling index. An increase in intimal and medial thickness was found in all vein grafts. However, intimal thickness was significantly reduced in the grafts treated with Egr-1 decoy ODN, whereas luminal area was significantly increased.ConclusionA single intra-operative pressure-mediated transfection of vein grafts with Egr-1 decoy ODN significantly suppresses intimal hyperplasia in a rabbit hypercholesterolaemic model