Adventitial Paclitaxel to Delay Post-Intervention Dialysis Graft Stenosis

描述（由申请人提供）：由于透析通路移植物的移植物-静脉吻合处狭窄导致的血液透析血管通路功能障碍目前是美国估计350，000例血液透析患者的一个巨大临床问题。尽管问题的严重性，目前还没有有效的治疗这种情况。透析通路狭窄是由于新生内膜增生，传统上认为是由于平滑肌细胞从中膜迁移到内膜。最近的数据表明，外膜也通过促进新生内膜细胞体积和不良血管重塑在此过程中发挥重要作用。在当前提案中，我们假设透析通路移植物是使用创新药物输送平台（Mercator MedSystems MicroSyringe Infusion Catheter（TM））进行抗狭窄药物局部外膜输送的理想临床模型。这是一种血管内球囊导管，当球囊充盈时，通过血管壁挤出针头，从而允许直接进入外膜进行治疗。在特定目标1中，我们计划在经验证的猪动静脉移植物狭窄模型中评估紫杉醇血管摄取的幅度和持续时间，同时使用三种不同剂量的紫杉醇。这些信息将使我们能够确定适当剂量的紫杉醇，能够在血管壁内达到抗增殖浓度，并具有最小的局部或全身毒性。然后将确定的剂量用于第二组实验（特定目标2），其中在动静脉移植物狭窄的血管成形术后模型中，将通过MicroSyringe器械输注到移植物-静脉吻合口的紫杉醇与对照血管周围输注（使用各种组织形态学和分子终点）进行比较。我们认为，该提案的重要性在于：（a）我们计划针对棘手的临床问题测试一种新型的创新性局部给药装置（B）透析通路移植物可能是测试本提案中描述的新型局部治疗的理想临床模型（c）与血管内治疗相比，血管周围或外膜治疗在预防和治疗血管狭窄方面可能更有效（特别是关于最近对药物洗脱支架中晚期血栓形成的关注）和（d）在透析通路功能障碍的情况下的治疗成功可以迅速转化为以血管狭窄为特征的其他临床情况，狭窄事实上，如果这些初步试验研究成功，上述所有内容都表明Mercator MedSystems设备具有巨大的商业潜力。

DESCRIPTION (provided by applicant): 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.