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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的 Cylerus, Inc. 正在开发一种可植入的西罗莫司洗脱袖带和储液器系统，并结合临床批准的药物泵，解决了人工血管移植失败的难题。血管移植物构建使用合成聚合物或天然静脉广泛应用于血管手术。最常见的适应症这些移植物包括： 1) 血液透析通路，其中血液通路通常是通过构建自体 AV 瘘或手术放置扩张聚四氟乙烯 (ePTFE) 血管移植物。各种因素决定着通路的选择，但在美国，目前大约有 100,000 个 ePTFE 移植物用于超过 400,000 名接受慢性血液透析的患者。维持血管通路的费用血液透析患者的收入令人震惊，目前仅在美国每年就超过 10 亿美元。 2) 周围血管疾病（PVD），是由于脂肪沉积物（斑块）在动脉内堆积而最终导致的限制或完全阻断血流。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的内膜病变。宿主血管（即远端移植物吻合口内膜增生）。平均 60% 的移植物用于 AV 访问，以及 20% 用于 PVD 应用程序，将在 1 年内失败，给医疗保健系统和医疗保健系统带来巨大成本相当大的患者发病率。 Cylerus 解决方案是局部递送众所周知的抗增殖药物，西罗莫司（雷帕霉素），直接穿过ePTFE移植物的多孔壁，从而实现高局部药物移植物吻合口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。由于西罗莫司有效抑制血管细胞增殖和内膜增生，因此它将维持移植物功能（即透析能力）通过延长移植物通畅和减少频繁移植物翻修的需要。西罗莫司类似物（依维莫司、佐他莫司等）目前用于 FDA 批准的药物洗脱支架，并具有成功地防止了支架血管狭窄（再狭窄），这一过程也是由于内膜增生。对于支架，西罗莫司的短期（<1 个月）洗脱是有效的，部分原因是支架具有表面积小，开放式结构；因此，支架通常通过覆盖而快速且完全地愈合血管内皮细胞，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，抑制持久的移植物内膜增生可能需要持续、长期的抗增殖药物治疗（可能数周至数月）持续时间），以显着延长移植物寿命，使其超过目前的平均寿命（12-18 个月）。因此，为了延长假体移植物的存活率，Cylerus 正在开发一种新型药物输送技术，该技术与专有的西罗莫司配方，在体温下可稳定一个月或更长时间，使用临床批准的技术，持续有效地长时间瞄准移植物吻合部位植入式泵。