Applied gene therapy in preclinical models of vascular injury

Atherosclerosis remains the major cause of morbidity and mortality in Western countries. Atherothrombotic complications, including vascular occlusions and severe narrowing of nutrient blood vessels in the cerebral, coronary, or peripheral circulation, usually require invasive revascularization strategies. As molecular mediators contributing to these complications are being identified in more representative experimental injury models, and as gene transfer platforms and vectors acquire improved safety and efficacy profiles, there is ground for cautious optimism that gene-based interventions will likely reduce the clinical burden of these diseases. Increased generation of reactive oxygen species in diseased atherosclerotic vessels has been implicated in vasospasm, exaggerated neointima formation, and enhanced thrombosis. Ex vivo pressurized vascular gene transfer in venous bypass grafts using antisense oligonucleotides directed against cell-cycle control genes can modify the venous graft's phenotype and confer clinical benefit with improved long-term graft survival. Alternatively, percutaneous intra-arterial gene transfer is feasible, but at relatively low transgene expression levels. Although this may suffice in the case of secreted gene products with marked paracrine or bystander effects, including nitric oxide synthase and heme oxygenase-1, drug- and gene-eluting stents may provide the preferred future vehicle for well-controlled, quantifiable, and safe vascular gene transfer. Continued efforts to improve gene transfer technology in diseased human vessels and to increase our understanding of molecular targets are required before the full therapeutic potential of vascular gene therapy can be realized.