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

抽象概括 有超过160万患有终末期肾病的患者， 血液透析。长期血管通路对于这些患者进行血液透析至关重要， 通过手术构建动静脉（AV）瘘或插入AV 移植物血管通路的失败导致了惊人的发病率，甚至死亡率， 这些病人。30%的患者AV移植物失败通常由吻合口狭窄引起 需要外科修复或血管成形术的血管内再通。目前没有AV 移植物可用于抗增殖治疗的长期递送。我们的长期目标是 AV移植物的产生，其防止再狭窄并可用于血液透析， 并发症。本提案的目的是评估基于亲和力的药物递送 用于西罗莫司的长期持续递送的涂层。核心假设是， 释放西罗莫司的包被AV移植物将抑制平滑肌内膜生长， 用于移植物狭窄，从而防止动静脉移植失败。这项工作将在两个 目的：1）产生基于亲和力的西罗莫司释放移植物;和2）体内概念验证 在猪髂动脉移植物模型中验证涂覆的AV移植物的抗增殖作用。 Affinity Therapeutics提出的工作是创新的;它代表了第一个能够 持续的局部给药以防止内膜增生。我们用一种新颖的方法 实现了治疗剂的高载量和长期持续释放， 其他的，只研究扩散系统。预期结局包括带涂层的AV移植物 能够释放西罗莫司90天，抑制平滑肌细胞增殖90 体内天数。这些结果将通过提供AV而对血管通路领域产生积极影响。 用于治疗性递送抗增殖剂的移植物装置。第二阶段今后的工作将把 将I期原理性猪体内研究转化为具有统计学效力的研究，以验证 移植物长期通畅。此外，Affinity Therapeutics将继续与 包括血管外科医生和心脏病专家在内的合作者将这些涂层血管 更接近临床试验的移植物。

Abstract Summary 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 rates 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 will 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 the 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 field 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 a statistically powerful study to validate long-term graft patency. In addition, Affinity Therapeutics will continue to work with collaborators, including vascular surgeons and cardiologists to bring these coated vascular grafts closer to a clinical trial.