Local Gene Transfer of phVEGF-2 Plasmid by Gene-Eluting Stents

Abstract

Background— Drug-eluting stents represent a useful strategy for the prevention of restenosis using various antiproliferative drugs. These strategies share the liability of impairing endothelial recovery, thereby altering the natural biology of the vessel wall and increasing the associated risk of stent thrombosis. Accordingly, we tested the hypothesis that local delivery via gene-eluting stent of naked plasmid DNA encoding for human vascular endothelial growth factor (VEGF)-2 could achieve similar reductions in neointima formation while accelerating, rather than inhibiting, reendothelialization. Methods and Results— phVEGF 2-plasmid (100 or 200 μg per stent)–coated BiodivYsio phosphorylcholine polymer stents versus uncoated stents were deployed in a randomized, blinded fashion in iliac arteries of 40 normocholesterolemic and 16 hypercholesterolemic rabbits. Reendothelialization was nearly complete in the VEGF stent group after 10 days and was significantly greater than in control stents (98.7±1% versus 79.0±6%, P <0.01). At 3 months, intravascular ultrasound analysis revealed that lumen cross-sectional area (4.2±0.4 versus 2.27±0.3 mm 2 , P <0.001) was significantly greater and percent cross-sectional narrowing was significantly lower (23.4±6 versus 51.2±10, P <0.001) in VEGF stents compared with control stents implanted in hypercholesterolemic rabbits. Transgene expression was detectable in the vessel wall along with improved functional recovery of stented segments, resulting in a 2.4-fold increase in NO production. Conclusions— Acceleration of reendothelialization via VEGF-2 gene–eluting stents provides an alternative treatment strategy for the prevention of restenosis. VEGF-2 gene–eluting stents may be considered as a stand-alone or combination therapy.

Release of Plasmid DNA from Intravascular Stents Coated with Ultrathin Multilayered Polyelectrolyte Films

“…6,[8][9][10][11][12][13][14] This past work has focused largely on the encapsulation of plasmid DNA in thin films of degradable polymer 8, 10-13 or the tethering of viruses to collagen-coated stents 9 or bare metal stents. 14 In the long term, methods for non-viral gene delivery have the potential to be safer than methods based on the use of viruses.…”

Cardiovascular gene delivery: The good road is awaiting☆

“…More recently, Losordo et al were able to deliver a vascular endothelial growth factor (VEGF)-2 plasmid in a vascular stent. They found that the treatment group had an improved completeness of endothelialization, improved luminal cross-sectional area and vessel function as measured by nitric oxide production in hypercholesterolemic rabbits [111]. This approach shows much promise as a delivery system, but single gene therapy may not yield straightforward results.…”

Endothelial Recovery

“…27 Capitalizing on the advent of stent technology capable of drug delivery, we have recently shown that gene-eluting stents coated with phVEGF-2 naked plasmid DNA accelerate reendothelialization and inhibit neointimal proliferation in a hypercholesterolemic rabbit iliac angioplasty model. 28 In the present issue of Circulation, Hedman et al 1 report the provocative results of a phase II, randomized, placebocontrolled, double-blind study designed to test the feasibility, tolerability, and efficacy of VEGF gene therapy to prevent restenosis after coronary stenting. Thus, another step toward ameliorating, rather than perturbing, the biology of the artery wall as a restenosis prevention strategy has been taken.…”