A pig model of vein graft disease applications for potential gene therapies

The development of an effective and safe gene therapy for prevention of vein graft failure, either acute or chronic, relies on the use of applicable and reproducible models of vein graft failure. Evaluation of potential new therapies usually involves assessment of beneficial phenotypic changes to vascular cells in isolated cells, in more complex organ cultures, and in in vivo models. We have extensively utilized gene transfer in isolated human vein vascular smooth muscle cells (SMCs) and endothelial cells (ECs) (1). Furthermore, we have extended our initial studies and evaluated potential gene therapies in a human saphenous vein organ culture model (2,3). The use of human saphenous vein, in this context, is advantageous as it is the most commonly used conduit for bypass grafting in the clinic. However, the organ culture model is static, and additionally studies need to be carried out in an in vivo model. In this chapter we describe a porcine model of vein graft neointima formation. Pig arteriovenous bypass grafting provides a reproducible model of intimal thickening, which is associated with late vein graft failure, and the effect of potential gene therapies can be assessed over long periods (up to 6 mo) (4; see Fig. 1). Furthermore, the saphenous vein is removed prior to grafting, and ex vivo genetic manipulation can be performed, providing a simple, controllable and safe method of gene transfer prior to grafting in vivo. Fig. 1. Neointima formation in porcine saphenous vein grafts. Removal of grafts at 7 d (A) and 28 d (B) reveals extensive and progressive neointima formation. The intimal/ medial border is indicated with arrows in each case. A, adventitia; M, media; I, intima.