Localized Delivery of Sirolimus to Hemodialysis Vascular Access Grafts

西罗莫司局部递送至血液透析血管通路移植物

• 批准号: 9262391
• 负责人: PRABIR ROY-CHAUDHURY
• 金额: $ 60.37万
• 依托单位: CYLERUS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262391
• 关键词: Address; Anastomosis - action; Anatomy; Angiography; Animals; Area; Arteries; Arteriovenous fistula; Blood; Blood Vessels; Blood flow; Body Temperature; Caliber; Caring; Catheters; Cell Proliferation; Central Vein; Chronic; Clinical; Contracts; Data; Deposition; Development; Devices; Dialysis procedure; Distal; Dose; Drug Delivery Systems; Drug Kinetics; Dyes; End stage renal failure; Excipients; FDA approved; Failure; Family suidae; Fistula; Formulation; Functional disorder; Graft Survival; Healthcare Systems; Hemodialysis; Histologic; Hyperplasia; Immunosuppression; Implantable Pump; Infection; Infusion procedures; Interruption; Legal patent; Lesion; Measures; Medicine; Modeling; Morbidity - disease rate; Names; Operative Surgical Procedures; Outcome; Patients; Peripheral Vascular Diseases; Pharmaceutical Preparations; Pharmacotherapy; Phase; Polymers; Polytetrafluoroethylene; Positioning Attribute; Process; Production; Prosthesis; Pump; Rattus; SDZ RAD; Safety; Silicones; Sirolimus; Site; Smooth Muscle Myocytes; Solubility; Stenosis; Stents; Structure; Surface; System; Technology; Testing; Thrombosis; Time; Variant; Vascular Endothelial Cell; Vascular Graft; Vein graft; Veins; analog; biomaterial compatibility; cell motility; clinical development; cost; experimental study; graft failure; graft function; healing; high risk; high risk population; improved; in vivo; innovative technologies; man; migration; novel; novel therapeutics; patient population; prevent; restenosis; safety study; stability testing

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.

摘要 Cylerus，Inc.正在开发一种可植入的西罗莫司洗脱袖带和储药器系统， 批准的药物泵，以解决人工血管移植失败的难题。构建的血管移植物 使用合成聚合物或天然静脉广泛用于血管外科手术。最常见的适应症 1）血液透析通路，其中血液通路典型地通过构建 自体动静脉瘘或外科植入膨体聚四氟乙烯（ePTFE）血管移植物。 各种因素决定了入路的选择，但在美国，目前约有100，000个ePTFE移植物 用于超过40万名接受长期血液透析的患者。维持血管通路的成本 血液透析患者的费用惊人，仅在美国每年就超过10亿美元。2)外周血管 动脉粥样硬化性疾病（PVD），其由动脉内脂肪沉积物（斑块）的积累引起， 限制或完全阻断血液流动。当用于AV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手术连接处附近出现狭窄内膜病变 宿主血管（即，远端移植物吻合口内膜增生）。平均而言，AV中使用的移植物的60% 20%用于PVD应用，将在1年内失效，给医疗保健系统带来巨大成本， 相当高的患者发病率。Cylerus的解决方案是局部输送众所周知的抗增殖药物， 西罗莫司（雷帕霉素），直接通过多孔壁的ePTFE移植物，从而实现高局部药物 在移植物吻合和邻近血管部位的浓度，同时最大限度地减少循环药物水平。 由于西罗莫司能有效抑制血管细胞增殖和内膜增生， (i.e.,透析的能力）。帕霉素 类似物（依维莫司、佐他莫司等）目前用于FDA批准的药物洗脱支架， 成功地防止了支架血管的狭窄（再狭窄），这一过程也是由于内膜 增生对于支架，短期（<1个月）洗脱西罗莫司是有效的，部分原因是支架具有 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，这是一个中断内膜增生的过程。相反，由于人工血管 移植物很少完全愈合或完全内皮化其流动表面，抑制持续的移植物内膜 增生可能需要持续的、长期的抗增生药物治疗（可能是数周至数月 持续时间），以显著延长移植物寿命超过目前的平均值（12-18个月）。因此，委员会认为， 为了延长假体移植物的存活率，Cylerus正在开发一种新的药物输送技术， 西罗莫司专利制剂，在体温下稳定一个月或更长时间， 使用经临床批准的 可植入泵。