Novel antithrombotic agents to prevent hemodialysis vascular access failure

描述（由申请人提供）：目前，超过60%需要长期血液透析的终末期肾病患者通过自体动静脉内瘘（AVF）或合成移植物（AVG）进入。不幸的是，AVF创建后6个月的原发性失败率高达60%，AVG构建后1年的原发性失败率高达77%。手术创伤、反复针刺、机械剪切应力、外来移植物材料和尿毒症可引起强烈的血栓形成反应，形成富含纤维蛋白和血小板的壁基质，在其上发生过度细胞迁移、增殖和基质沉积，导致AVF和AVG吻合口周围区域的新生内膜增生（NH）。 因此，限制附壁血栓形成的早期事件可以有效地减少NH，这是狭窄和随后的透析通路失败的主要原因。然而，目前可用的抗血小板和抗凝药物在临床安全剂量下预防NH的有效性不足。 EVAS Therapeutics开发了两种血栓形成位点靶向融合蛋白（ANV-6L 15和TAP-ANV），它们可以特异性地对接到血栓形成细胞的膜表面，并钝化启动和传播凝血级联的膜相关酶/辅因子复合物。由于它们的高亲和力血栓形成位点靶向特性和相对短的循环半衰期，融合蛋白可以发挥持久的抗血栓形成作用而无需全身抗凝。这可能消除对长期抗血栓治疗的需要，并更有效地抑制附壁血栓形成，降低出血风险。该提案的主要目标是开发这些有前途的候选药物，用于预防NH和改善AVG的功能和生存。如果成功，这种策略可以应用于AVF。具体目标1：建立ANV-6L 15和TAP-ANV生产的中试规模工艺。 第一阶段开发的实验室工艺将适用于重组蛋白的中试规模生产。具体目标2：检查TAP-ANV和ANV-6L 15在猪血液透析血管通路模型中的治疗效果。将使用猪动静脉聚四氟乙烯（PTFE）移植物（AVG）模型检查NH形成和管腔通畅性。 目前还没有有效的治疗方法来提高血液透析动静脉通路的寿命。 通过这项研究，我们可以提供一种新的和简单的治疗干预，以提高血液透析PTFE AVG和AVF的寿命。本研究的结果还将为IND申报和进一步的临床开发提供关键数据。 公共卫生相关性：血液透析程序的执行需要功能性血管通路，通常在一年内失败。 本项目将研究两种新型抗血栓药物候选物在预防血液透析动静脉移植物衰竭中的疗效。

DESCRIPTION (provided by applicant): Currently, more than 60 % of end-stage renal diseases patients who require chronic hemodialysis are accessed through a native arteriovenous fistula (AVF) or synthetic graft (AVG). Unfortunately, primary failure rates were as high as 60 % at 6 months after AVF creation and 77% at 1 year after AVG construction. Surgical trauma, repeated needle punctures, mechanical shear stress, the foreign graft material and uremia can elicit a strong thrombotic response that lays down a mural fibrin- and platelet-rich substrate on which excessive cell migration, proliferation and matrix deposition occur, leading to neointimal hyperplasia (NH) in the peri-anastomotic regions of AVFs and AVGs. Limiting the early event of mural thrombosis may thus effectively reduce NH, which is the primary cause of stenosis and subsequent dialysis access failure. Currently available antiplatelet and anticoagulant drugs, however, have inadequate efficacies in preventing NH at clinically safe doses. EVAS Therapeutics has developed two thrombogenic site-targeted fusion Proteins (ANV-6L15 and TAP-ANV), which can specifically dock onto the membrane surfaces of thrombogenic cells and passivate the membrane-associated enzyme/cofactor complexes that initiate and propagate the clotting cascade. Due to their high-affinity thrombogenic site-targeting properties and relatively short circulating half-lives, the fusion proteins can exert long-lasting antithrombotic effect without systemic anticoagulation. This may eliminate the need for long-term antithrombotic therapy and inhibit mural thrombosis more effectively with reduced risks of bleeding. The main objective of this proposal is to develop these promising drug candidates for prevention of NH and improving the function and survival of AVGs. If successful, this strategy can be applied to AVFs. The specific aims of the phase II proposal are: Specific aim 1: Establish pilot-scale processes for production of ANV-6L15 and TAP-ANV. A bench process developed in phase I will be adapted for pilot-scale production of the recombinant proteins. Specific aim 2: Examine therapeutic efficacies of TAP-ANV and ANV-6L15 in porcine hemodialysis vascular access models. Both NH formation and lumen patency will be examined using a porcine arteriovenous polytetrafluoroethylene (PTFE) graft (AVG) model. Currently there are no effective therapies to improve hemodialysis arteriovenous access longevity. Through this study we may provide a novel and simple therapeutic intervention to improve longevity of hemodialysis PTFE AVGs and AVFs. Results from this study will also provide critical data for IND filing and further clinical development. PUBLIC HEALTH RELEVANCE: Performance of hemodialysis procedure requires a functional vascular access which often fails within one year. This project will examine the therapeutic efficacy of two novel antithrombotic drug candidates in preventing hemodialysis arteriovenous graft failure.