Affinity-based delivery of Sirolimus for prevention of AV graft failure

描述(申请人提供)：超过160万名终末期肾病患者需要血液透析。长期的血管通路对于这些患者进行血液透析至关重要，可以通过外科手术建立动静脉(AV)瘘或植入动静脉移植物来获得。在这些患者中，血管通路的失败导致了惊人的发病率甚至死亡率。在需要外科翻修或血管内再通行血管成形术的患者中，30%的患者的房室移植失败通常是由于吻合口狭窄所致。目前，尚无房室移植物可用于长期提供抗增殖治疗。我们的长期目标是开发出能够防止再狭窄并可用于血液透析而不会出现并发症的房室移植物。这项建议的目的是评估基于亲和力的药物释放涂层对西罗莫司的长期、持续释放。中心假设是，释放西罗莫司的涂层房室移植物将抑制移植物狭窄的主要罪魁祸首--平滑肌内膜生长，从而防止房室移植物失败。这项工作将在两个方面完成：1)生产基于亲和力的西罗莫司 释放移植物；以及2)在猪的髂骨移植物模型中，对TH包被的AV移植物的抗增殖作用进行体内概念验证。亲和治疗公司提出的工作具有创新性； 它代表了第一个能够持续、局部给药预防内膜增生的房室移植物。我们使用一种新的方法来实现高负载和长期、持续的治疗药物释放，远远超过其他研究的仅扩散系统的能力。预期的结果包括能够释放西罗莫司90天的涂层AV移植物，在体内抑制血管细胞增殖90天。这些结果将对血管通路领域产生积极影响，因为它为抗增殖剂的治疗性输送提供了一种血管移植装置。第二阶段的未来工作将把第一阶段的猪体内原则性证明研究转化为验证长期移植物通畅性的统计功能强大的研究。此外，亲和治疗公司将继续与包括血管外科医生和心脏病学家在内的合作者合作，使这些涂层血管移植物更接近临床试验。

DESCRIPTION (provided by applicant): There are greater than 1.6 million patients that suffer end stage renal disease requiring hemodialysis. Long term vascular access is vital for these patients to undergo hemodialysis and is obtained via surgical construction of an arteriovenous (AV) fistula or interposition of an AV graft. Failure of vascular access results in staggering rate of morbidity and even mortality in these patients. AV graft failure typically results from anastomotic stenosis in 30% of patients requiring surgical revision or endovascular recanalization with angioplasty. Currently, no AV graft is available for the long-term delivery of antiproliferative therapies. Our long-term goal is the generation of AV grafts which prevent restenosis and can be used for hemodialysis without ensuing complications. The objective of this proposal is to evaluate affinity-based drug delivery coatings for the long-term, sustained delivery of sirolimus. The central hypothesis is that that coated AV grafts releasing sirolimus wil inhibit smooth muscle intimal growth, the main culprit for stenosis in grafts, and thus prevent AV graft failure. This work will be accomplished in two aims:1) Production of affinity-based sirolimus releasing grafts; and 2) proof-of-concept in vivo validation of the anti-proliferative effect of th coated AV graft in a porcine iliac graft model. Affinity Therapeutics' proposed work is innovative; it represents the first AV graft capable of sustained, local drug delivery for preventing intimal hyperplasia. We use a novel approach to achieve high loading and long-term, sustained release of therapeutics well beyond that capable of other, diffusion-only systems studied. The expected outcomes include a coated AV graft capable of releasing sirolimus for 90 days that inhibits smooth muscle cell proliferation for 90 days in vivo. These results will positively impact the fiel of vascular access by providing an AV graft device for therapeutic delivery of antiproliferatives. Future work in Phase II will translate the Phase I proof-of-principle porcine in vivo studies into statistically powerful study to validate long-term graft patency. In addition, Affinity Therapeutic will continue to work with collaborators, including vascular surgeons and cardiologists to bring these coated vascular grafts closer to a clinical trial.