Localized Statin Delivery for Prevention of Primary AV Fistula Failure

摘要摘要 动静脉瘘(AVF)是血液透析患者首选的血管通路方式，但 约60%的AVF未成熟，成熟的AVF 1年后仅有60%的AVF未成熟。血管通路 包括动静脉瘘在内的心衰是由新生内膜增生引起的，每年造成10亿美元的损失。 血管通路故障造成的成本，包括20%的血液透析患者住院费用。全身他汀类药物 众所周知，动脉旁路移植术中的治疗有助于预防新生内膜增生，最近对 大约10,000名患者显示AVF失败减少了21%，这与他汀类药物的特性和剂量密切相关。 来自Sanjay Misra博士实验室的最新证据表明，全身他汀类药物能够显著减少 小鼠慢性肾脏病aVF模型中的新生内膜增生。亲和力旨在创造他汀类药物 可以注射到动静脉流出道外膜的微粒，以防止 在数周内局部注射他汀类药物，从而消除潜在的血管内膜增生 他汀类药物的副作用和增效作用。我们的长期目标是开发可注射的 能够防止新生内膜增生的微粒。这项提议的目标是产生 加载他汀类药物的可注射微粒可防止因新生内膜增生而导致的动静脉动静脉瘘失败。中环 假设他汀类药物在几周内局部给药会增加管腔 通过阻止成纤维细胞向肌成纤维细胞转化和预防 平滑肌细胞的增殖，从而减少静脉流出道的新生内膜面积。这 工作将在三个方面完成：1)验证他汀类药物的体外载药和释放；2)验证他汀类药物 利用体外低氧成纤维细胞建立肌成纤维细胞分化模型；3)最小化 活体动静脉瘘形成后的静脉内膜增生。 我们提出的工作是创新的，使用可注射的微粒将他汀类药物直接输送到静脉 流出道组织，防止新生内膜增生。我们使用一种新的方法来实现高负载 以及以消除任何潜在全身副作用的方式长期、持续地服用他汀类药物。 预期的结果包括能够在体外释放他汀类药物28天的可注射微粒 并在体内防止新生内膜增生至少28天。这些结果将对 降低动静脉瘘和动静脉动静脉移植物因新生内膜而失败率的血管通路领域 增生症。第二阶段的未来工作将把这些加载他汀类药物的可注射微粒从 第一阶段概念验证在猪身上进行了一项统计上强有力的研究，其中血管系统和 血液动力学与人类最相似。

Abstract Summary Arteriovenous fistulas (AVFs) are the preferred vascular access mode for hemodialysis patients, but ~60% of AVFs fail to mature and only ~60% of mature AVFs are patent after 1 year. Vascular access failure, including AVFs, results from neointimal hyperplasia and contributes to >$1 billion USD annual costs from vascular access failure including 20% of hemodialysis patient hospitalizations. Systemic statin treatment is known to help prevent neointimal hyperplasia in arterial bypass grafting, and recent study of ~10,000 patients showed a 21% reduction in AVF failure that was strongly tied to statin identity and dose. Recent evidence from Dr. Sanjay Misra’s lab shows that systemic statins were able to significantly reduce neointimal hyperplasia in a mouse chronic kidney disease AVF model. Affinity aims to create statin-loaded microparticles that can be injected into the adventitia of the venous outflow tract of the AVF to prevent neointimal hyperplasia by locally delivering statins over the course of weeks thereby eliminating potential side effects and increasing efficacy of statin action. Our long-term goal is to develop injectable microparticles capable of preventing neointimal hyperplasia. The objective of this proposal is to produce statin-loaded, injectable microparticles to prevent AVF failure due to neointimal hyperplasia. The central hypothesis is that localized delivery of statins over the course of several weeks will increase the lumen area of the venous outflow tract by preventing fibroblast conversion to myofibroblasts and preventing proliferation of smooth muscle cells thereby decreasing neointimal area in the venous outflow tract. This work will be accomplished in three aims: 1) Validate statin loading and delivery in vitro; 2) Validate statin delivery on a model of myofibroblast differentiation using hypoxic fibroblasts in vitro; and 3) Minimize venous neointimal hyperplasia following AVF creation in vivo. Our proposed work is innovative using injectable microparticles to deliver statins directly to the venous outflow tract tissue to prevent neointimal hyperplasia. We use a novel approach to achieve high loading and long-term, sustained delivery of statins in a mode that eliminates any potential systemic side effects. The expected outcomes include injectable microparticles capable of release statin for >28 days in vitro and preventing neointimal hyperplasia for at least 28 days in vivo. These results will positively impact the field of vascular access by decreasing failure rates for both AVFs and AV grafts due to neointimal hyperplasia. Future work in Phase II will translate these statin-loaded, injectable microparticles from this Phase I proof-of-concept work into a statistically powerful study in pigs where the vasculature and hemodynamics are most similar to those in humans.