Localized Delivery of Sirolimus to Hemodialysis Vascular Access Grafts

摘要 Cylerus，Inc.正在开发一种可植入的西罗莫司洗脱袖带和储罐系统，与临床上的 批准的药物泵，解决了人工血管移植失败的难题。构建血管移植物 使用合成聚合物或天然静脉在血管外科中被广泛使用。最常见的适应症 用于这些移植物的是：1)血液透析通路，其中血液通路通常通过构建 自体房室瘘或手术植入扩张的聚四氟乙烯(EPTFE)血管移植物。 各种因素制约着接入的选择，但在美国，目前约有100,000枚ePTFE移植物 用于40多万名接受慢性血液透析的患者。在中国维持血管通路的成本 血液透析患者令人震惊，现在仅在美国一年就超过10亿美元。2)外周血管 疾病(PVD)，由动脉内脂肪沉积(斑块)积聚所致，最终 限制或完全阻断血液流动。当用于房室通路和PVD应用时，ePTFE血管移植物 最常见的是在移植物和移植物之间的下游外科交界处附近发生狭窄的内膜病变。 宿主血管(即移植物远端吻合口内膜增生)。平均而言，60%的移植物用于AV 访问(其中20%用于PVD应用程序)将在1年内失败，医疗保健系统和 相当多的病人发病率。Cylerus的解决方案是在当地提供著名的抗增殖药物， 西罗莫司(雷帕霉素)，直接通过ePTFE的多孔壁，从而获得高局部药物 在移植吻合口和邻近血管部位的药物浓度，同时将循环药物浓度降至最低。 由于西罗莫司有效地抑制血管细胞增殖和内膜增生，因此它将维持移植物的功能。 通过延长移植物的通畅性和减少频繁的移植物翻修的需要，来提高(即透析的能力)。西罗莫司 类似物(伊维洛莫斯、Zotarolimus等)目前用于FDA批准的药物洗脱支架，并已 成功地预防了支架血管的狭窄(再狭窄)，这一过程也是由于血管内膜 增生症。对于支架，西罗莫司的短期(1个月)洗脱是有效的，部分原因是支架有 较小的表面积和开放的结构；因此，支架通常通过覆盖 血管内皮细胞，这是一种阻断内膜增生的过程。相反，因为人造血管 移植物很少完全愈合或完全内皮化，抑制永久性移植物内膜。 增生症可能需要持续的、更长期的抗增殖药物治疗(可能需要几周到几个月 在持续时间上)，以便显著延长移植物的寿命，超过目前的平均寿命(12-18个月)。因此， 为了延长假体的存活时间，Cylerus正在开发一种新的药物输送技术，将 专利西罗莫司配方，可在体温下稳定一个月或更长时间，可以 持续有效地定向移植吻合口，延长使用临床批准的 植入式泵。

Abstract Cylerus, Inc., is developing an implantable, sirolimus-eluting cuff and reservoir system, combined with a clinically approved drug pump, to solve the difficult problem of prosthetic vascular graft failure. Vascular grafts constructed using either synthetic polymers or native veins are widely used in vascular surgery. The most common indications for these grafts are: 1) Hemodialysis access, in which blood access is typically achieved by construction of an autogenous AV fistula or surgical placement of an expanded polytetrafluoroethylene (ePTFE) vascular graft. Various factors govern the choice of access, but in the US approximately 100,000 ePTFE grafts are currently utilized in over 400,000 patients undergoing chronic hemodialysis. The costs of maintaining vascular access in hemodialysis patients are staggering, and now exceed $1 billion annually in the US alone. 2) Peripheral vascular disease (PVD), which results from the accumulation within arteries of fatty deposits (plaque) that ultimately restrict or completely block blood flow. When used in AV access and PVD applications, ePTFE vascular grafts most commonly develop stenotic intimal lesions near the downstream surgical junction between the graft and host blood vessel (i.e., distal graft anastomotic intimal hyperplasia). On average, 60% of grafts used in AV access, and 20% used in PVD applications, will fail within 1 year, with large costs to the healthcare system and considerable patient morbidity. The Cylerus solution is to locally deliver the well-known anti-proliferative drug, sirolimus (rapamycin), directly through the porous wall of ePTFE grafts, thereby achieving high local drug concentrations at the graft anastomosis and adjacent vascular sites while minimizing circulating drug levels. Since sirolimus potently inhibits vascular cell proliferation and intimal hyperplasia, it will sustain graft function (i.e., ability to dialyze) by prolonging graft patency and reducing the need for frequent graft revision. Sirolimus analogs (everolimus, zotarolimus, etc.) are currently utilized in FDA approved, drug-eluting stents and have successfully prevented the narrowing of stented vessels (restenosis), a process that is also due to intimal hyperplasia. With stents, short-term (<1 month) elution of sirolimus is effective, in part, because stents have a small surface area and open structure; consequently, stents often heal quickly and completely by coverage with vascular endothelial cells, a process that interrupts intimal hyperplasia. Conversely, because prosthetic vascular grafts rarely heal completely or fully endothelialize their flow surfaces, inhibition of persistent graft intimal hyperplasia will likely require continuous, longer-term, anti-proliferative drug therapy (perhaps weeks-to-months in duration) in order to significantly prolong graft lifetimes beyond current averages (12-18 months). Accordingly, to prolong prosthetic graft survival Cylerus is developing a novel drug delivery technology combined with a proprietary sirolimus formulation, which is stable at body temperature for a month or more, that can be continuously and efficiently targeted to graft anastomotic sites for extended periods using a clinically approved implantable pump.