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). The primary objective of this first multicenter, prospective, single-blind, dose escalation study was to obtain safety and tolerability information of the iNOS lipoplex (CAR-MP583) gene therapy for reducing restenosis following PCI. Local coronary intramural CAR-MP583 delivery was achieved using the Infiltrator balloon catheter. A total of 30 patients were treated in the study (six patients, 0.5 μg; six patients, 2.0 μg; six patients, 5.0 μg; and 12 patients, 10 μg). There were no complications related to local application of CAR-MP583. In one patient, PCI procedure-related transient vessel occlusion occurred with consecutive troponin elevation. There were no signs of inflammatory responses or hepatic or renal toxicity. No dose relationship was seen with regard to adverse events across the dose groups. Thus, coronary intramural lipoplex-enhanced iNOS gene therapy during PCI is feasible and appears to be safe. These initial clinical results are encouraging to support further clinical research, in particular in conjunction with new local drug delivery technologies.