Localized Statin Delivery for Prevention of Primary AV Fistula Failure

抽象概括 动静脉内瘘（AVF）是血液透析患者的首选血管通路模式，但 约60%的AVF未能成熟，仅约60%的成熟AVF在1年后通畅。血管通路 包括AVF在内的衰竭是由新生内膜增生引起的，每年造成的损失超过10亿美元 血管通路故障的成本，包括20%的血液透析患者住院。全身他汀类 已知治疗有助于防止动脉旁路移植术中的新生内膜增生， 约10，000例患者显示AVF失败减少了21%，这与他汀类药物的特性和剂量密切相关。 Sanjay Misra博士实验室的最新证据表明，全身性他汀类药物能够显著降低 小鼠慢性肾病AVF模型中的新生内膜增生。Affinity旨在创建他汀类药物负载 可以注射到AVF的静脉流出道的外膜中以防止AVF的发生。 通过在数周内局部递送他汀类药物，从而消除了可能的新生内膜增生 副作用和增加他汀类药物作用的功效。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。该提案的目的是产生 载他汀类药物的可注射微粒，以预防由于新生内膜增生导致的AVF失败。中央 假设在几周内局部递送他汀类药物将增加管腔 通过防止成纤维细胞转化为肌成纤维细胞和防止 平滑肌细胞增殖，从而减少静脉流出道中的新生内膜面积。这 本论文的主要工作包括三个方面：1）体外载药和释放; 2）体外释放 在体外使用低氧成纤维细胞的肌成纤维细胞分化模型上递送;和 体内AVF形成后静脉新生内膜增生。 我们提出的工作是创新性的，使用可注射微粒将他汀类药物直接输送到静脉 流出道组织，以防止新生内膜增生。我们使用一种新颖的方法来实现高负载 以及以消除任何潜在的全身性副作用的方式长期持续递送他汀类药物。 预期的结果包括能够在体外释放他汀类药物超过28天的可注射微粒 并在体内防止新生内膜增生至少28天。这些成果将对 通过降低AVF和AV移植物由于新生内膜 增生未来的工作在第二阶段将翻译这些他汀类药物加载，注射微粒从这个 I期概念验证工作进入猪的统计学上强大的研究，其中血管和 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.