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

描述（由申请人提供）：有超过160万名患有需要血液透析的终末期肾病的患者。长期血管通路对于这些患者进行血液透析至关重要，可通过手术构建动静脉（AV）瘘或插入AV移植物获得。血管通路的失败导致这些患者的发病率甚至死亡率惊人。在30%需要手术翻修或血管成形术血管内再通的患者中，AV移植物失效通常是由吻合口狭窄引起的。目前，没有AV移植物可用于长期递送抗增殖治疗。我们的长期目标是生产防止再狭窄的AV移植物，并可用于血液透析而不会产生并发症。本提案的目的是评估西罗莫司长期持续给药的亲和性药物递送涂层。中心假设是，释放西罗莫司的涂层AV移植物将抑制平滑肌内膜生长，这是移植物狭窄的主要原因，从而防止AV移植物衰竭。本工作主要完成两个方面的工作：1）西罗莫司亲和素的制备 释放移植物;和2）在猪髂动脉移植物模型中对涂覆的AV移植物的抗增殖作用的概念验证。Affinity Therapeutics提出的工作是创新的; 它代表了第一个能够持续局部给药以防止内膜增生的AV移植物。我们使用一种新的方法来实现高负荷和长期，持续释放的治疗远远超过其他的能力，仅扩散系统的研究。预期结果包括能够释放西罗莫司90天的涂层AV移植物，其在体内抑制平滑肌细胞增殖90天。这些结果将通过提供用于抗增殖剂的治疗性递送的AV移植物装置而对血管通路领域产生积极影响。II期的未来工作将把I期原理证明猪体内研究转化为统计学上有效的研究，以验证长期移植物通畅性。此外，Affinity Therapeutic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.