Hemodialysis vascular access dysfunction as a result of stenosis at the graft-vein anastomosis of dialysis access grafts is currently a huge clinical problem for the estimated 350,000 patients on hemodialysis in the United States. Despite the magnitude of the problem there are currently no effective therapies for this condition. Dialysis access stenosis is due to neointimal hyperplasia which has traditionally been thought to be due to the migration of smooth muscle cells from the media into the intima. Recent data suggests that the adventitia also plays an important role in this process by contributing to both neointimal cell volume and adverse vascular remodeling. In the current proposal we hypothesize that dialysis access grafts are the ideal clinical model for local adventitial delivery of anti-stenotic drugs using an innovative drug delivery platform (the Mercator MedSystems MicroSyringe Infusion Catheter(tm)). This is an endovascular balloon catheter which extrudes a needle through the vessel wall when the balloon is inflated, thus allowing direct therapeutic access to the adventitia. In Specific Aim 1 we plan to assess the magnitude and duration of vascular uptake of paclitaxel in a validated pig model of arteriovenous graft stenosis, while using three different doses of paclitaxel. This information will allow us to identify an appropriate dose of paclitaxel that is able to achieve antiproliferative concentrations within the vessel wall with minimal local or systemic toxicity. The identified dose will then be used in a second set of experiments (Specific Aim 2), in which paclitaxel infused through the MicroSyringe device into the graft-vein anastomosis will be compared to control perivascular infusions (using a variety of histomorphometric and molecular end points) in a post-angioplasty model of arteriovenous graft stenosis. We believe that the significance of this proposal lies in the fact that (a) we plan to test out a novel and innovative local drug delivery device for a recalcitrant clinical problem (b) dialysis access grafts could be the ideal clinical model for testing out novel local therapies such as those described in this proposal (c) perivascular or adventitial therapy may be more effective in the prevention and treatment of vascular stenosis as compared to endovascular therapies (particularly with regard to recent concerns about late thromboses in the setting of drug eluting stents) and (d) therapeutic success in the setting of dialysis access dysfunction could be rapidly translated to other clinical settings characterized by vascular stenosis such as coronary and peripheral stenoses. Indeed, all of the above suggest a huge commercial potential for the Mercator MedSystems device, if these initial pilot studies are successful
