A prospective, single-blind, multicenter, dose escalation study of intracoronary iNOS lipoplex (CAR-MP583) gene therapy for the prevention of restenosis in patients with de novo or restenotic coronary artery lesion (REGENT I extension).

Neointimal hyperplasia causing recurrent stenosis is a limitation of the clinical utility of percutaneous transluminal coronary interventions (PCI). Nitric oxide (NO) inhibits smooth muscle cell proliferation, platelet activation, and inflammatory responses, all of which have been implicated in the pathogenesis of restenosis. In animals, neointimal proliferation after balloon injury has been shown to be effectively reduced by gene transfer of the inducible NO synthase (iNOS).

Cell cycle-dependent regulation of smooth muscle cell activation.

Objective: Although numerous diseases involving cellular proliferation are also associated with phenotypic changes, there has been little direct evidence that cell phenotype and the cell's response to external stimuli are modified during passage through different phases of the cell cycle. In this study, we demonstrate that an association exists between cell cycle progression and the expression of genes involved in cellular activation.

Methods And Results: Early cell cycle arrest of aortic smooth muscle cells was found to inhibit the tumor necrosis factor alpha (TNFalpha)-induced upregulation of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, important markers of vascular cell activation in diseases such as atherosclerosis.

Preclinical evaluation of inducible nitric oxide synthase lipoplex gene therapy for inhibition of stent-induced vascular neointimal lesion formation.

Several reports have established the concept of nitric oxide synthase (NOS) gene transfer for inhibiting smooth muscle cell (SMC) proliferation after vascular injury. To minimize potential risks associated with viral gene transfer, we developed a liposome-based gene transfer approach employing inducible NOS (iNOS) overexpression for inhibition of stent-induced neointimal lesion formation. Therapeutic lipoplexes were transferred to femoral or coronary arteries of Goettingen minipigs, using the Infiltrator local drug delivery device.

CCAAT/enhancer-binding protein decoy oligodeoxynucleotide inhibition of macrophage-rich vascular lesion formation in hypercholesterolemic rabbits.

Many cytokine genes, including those encoding acute-phase proteins and immunoglobulins, share binding sites for the CCAAT/enhancer-binding protein (C/EBP) in their 5'-flanking regions, and C/EBP-related transcription factors regulate cell proliferation during terminal differentiation. Therefore, C/EBP represents an attractive target for inhibiting restenosis after balloon angioplasty. In a rabbit model of restenosis that combines balloon injury of the carotid artery with cholesterol-mediated chronic inflammation, a decoy oligodeoxynucleotide (ODN) capable of neutralizing C/EBP was administered to the site of injury for 30 minutes.