Catheter-based adenovirus-mediated anti-monocyte chemoattractant gene therapy attenuates in-stent neointima formation in cynomolgus monkeys

We have previously demonstrated great benefit from anti-monocyte chemoattractant protein-1 (MCP-1) gene therapy by “systemic” transfer of an N-terminal deletion mutant of human MCP-1 (called 7ND) gene into skeletal muscle for treatment of restenosis and atherosclerosis. However, recent evidence suggests that “local” gene transfer may be a clinically relevant approach. We therefore tested the hypothesis that catheter-based adenovirus-mediated anti-MCP-1 gene therapy attenuates stent-associated neointima formation.Bare metal stents were implanted in iliac arteries of cynomolgus monkeys fed a high cholesterol diet. Immediately after the stenting procedure, normal saline or recombinant adenoviral vector containing LacZ or the 7ND gene was administered locally into the stenting site through a Remedy channel-delivery catheter. Compared to saline infusion or LacZ gene transfer, 7ND gene transfer markedly reduced inflammatory changes at an early stage and attenuated neointima formation after 4 weeks. This strategy also reduced the increased production of pro-inflammatory and growth-promoting factors such platelet-derived growth factor. No systemic adverse effects of 7ND gene transfer were detected. There were no significant differences in serum cholesterol levels among the three groups.These data suggest that catheter-based adenovirus-mediated anti-MCP-1 gene therapy may be a clinically relevant and feasible strategy for treatment of in-stent restenosis.