Phosphodiesterase inhibitor-mediated potentiation of adenovirus delivery to myocardium

Current gene therapy models are limited by inadequate vector delivery. Incr eases in microvascular permeability have been shown to improve adenovirus-m ediated gone transfer to ex vivo and in vivo models. We explored the intrac ellular mechanism underlying the permeabilizing effects of vascular endothe lial growth factor (VEGF). Using an cs vivo model of coronary perfusion in rabbits. rue found a dose-response relationship between VEGF and the effici ency of adenoviral gene transfer. Inhibitors of nitric oxide synthase and g uanylate cyclase prevented the VEGF effect, and analogues of nitric oxide a nd cGMP mimicked the effect. Co-administration of phosphodiesterase 5 inhib itors and VEGF caused a synergistic increase in gene delivery. These result s can be readily applied to existing models to further optimize vector deli very for gene therapy. (C) 2001 Academic Press.