t-1032 and zaprinast

Current gene therapy models are limited by inadequate vector delivery. Increases in microvascular permeability have been shown to improve adenovirus-mediated gene transfer to ex vivo and in vivo models. We explored the intracellular mechanism underlying the permeabilizing effects of vascular endothelial growth factor (VEGF). Using an ex vivo model of coronary perfusion in rabbits, we found a dose-response relationship between VEGF and the efficiency of adenoviral gene transfer. Inhibitors of nitric oxide synthase and guanylate cyclase prevented the VEGF effect, and analogues of nitric oxide and cGMP mimicked the effect. Co-administration of phosphodiesterase-5 inhibitors and VEGF caused a synergistic increase in gene delivery. These results can be readily applied to existing models to further optimize vector delivery for gene therapy.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adenoviruses, Human; Animals; beta-Galactosidase; Cyclic GMP; Drug Synergism; Endothelial Growth Factors; Gene Transfer Techniques; Genes, Reporter; Genetic Vectors; Guanylate Cyclase; Heart; Humans; Isoquinolines; Lymphokines; Myocardium; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroglycerin; omega-N-Methylarginine; Phosphodiesterase Inhibitors; Piperazines; Purines; Purinones; Pyridines; Rabbits; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors