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

Abstract

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.

The cell cycle: A critical therapeutic target to prevent vascular proliferative disease

“…By using a local delivery balloon catheter, the neointimal volume obstruction and the angiographic restenosis rate wre not reduced (Table 1) (185). The clinical application of antisense ODN technology remains limited by a relative lack of specificity, slow uptake across the cell membrane and fast intracellular destruction of the ODN (186). It may be necessary to target more than one gene.…”

“…An advanced six-ring morpholino backbone c-myc antisense (AVI-4126 [Resten NG], AVI BioPharma, USA) with increased specificity was shown to inhibit c-myc expression and intimal hyperplasia after local catheter delivery in a porcine stent restenosis model (186). This new molecular configuration increased intracellular uptake, resisted enzymatic degradation and enhanced specificity to its target mRNA (186).…”

“…This new molecular configuration increased intracellular uptake, resisted enzymatic degradation and enhanced specificity to its target mRNA (186). Recently, the results of the AVAIL study, a phase II clinical trial evaluating intramural delivery of AVI-4126 in patients with focal de novo stenosis or ISR, were presented (188).…”

New Frontiers in Cardiology

“…C-myc antisense oligonucleotides have also been shown to inhibit inflammation and extracellular matrix production. 14 However, the first clinical experience using catheter-based local delivery of c-myc antisense oligonucleotides was disappointing. 15…”

Post-intervention vessel remodeling

“…Promising results have been obtained with antisense oligonucleotides against NF B, 24 E2F 25 and cmyc. 26 Also, adenoviral Gax (growth arrest homeobox) gene transfer has been shown to reduce neointimal hyperplasia in stented rabbit iliac arteries. 27 The plateletderived growth factor (PDGF) gene family is one of the most potent chemoattractants of vascular SMC.…”