Affinity-based delivery of Sirolimus for prevention of AV graft failure

基于亲和力的西罗莫司递送预防 AV 移植失败

• 批准号: 8918090
• 负责人: Sean T. Zuckerman
• 金额: $ 2.5万
• 依托单位: AFFINITY THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918090
• 关键词: Abate; Affinity; Angiography; Angioplasty; Animal Model; Arteriovenous fistula; Biological; Blood Vessels; Boston; Caliber; Caring; Cell Proliferation; Clinical Trials; Coagulation Process; Collaborations; Contralateral; Cyclodextrins; Data; Devices; Diffusion; Disease; Dose; Drug Delivery Systems; End stage renal failure; Failure; Family suidae; Funding; Future; Generations; Goals; Growth; Health; Hemodialysis; Histology; Hour; Hyperplasia; Implant; Incubators; Licensing; Marketing; Measures; Modeling; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Participant; Patients; Peripheral; Pharmaceutical Preparations; Phase; Polymers; Polytetrafluoroethylene; Prevention; Production; Public Health; Research Personnel; Second Look Surgery; Self-control as a personality trait; Sirolimus; Small Business Innovation Research Grant; Smooth Muscle; Smooth Muscle Myocytes; Stenosis; Surgeon; System; Technology; Testing; Therapeutic; Translating; United States National Institutes of Health; Universities; University Hospitals; Validation; Vascular Graft; Work; base; cell motility; cooking; cost; dosage; graft failure; implantation; in vivo; in vivo Model; innovation; local drug delivery; mortality; novel strategies; prevent; prototype; response to injury; restenosis; small molecule; success

DESCRIPTION (provided by applicant): There are greater than 1.6 million patients that suffer end stage renal disease requiring hemodialysis. Long term vascular access is vital for these patients to undergo hemodialysis and is obtained via surgical construction of an arteriovenous (AV) fistula or interposition of an AV graft. Failure of vascular access results in staggering rate of morbidity and even mortality in these patients. AV graft failure typically results from anastomotic stenosis in 30% of patients requiring surgical revision or endovascular recanalization with angioplasty. Currently, no AV graft is available for the long-term delivery of antiproliferative therapies. Our long-term goal is the generation of AV grafts which prevent restenosis and can be used for hemodialysis without ensuing complications. The objective of this proposal is to evaluate affinity-based drug delivery coatings for the long-term, sustained delivery of sirolimus. The central hypothesis is that that coated AV grafts releasing sirolimus wil inhibit smooth muscle intimal growth, the main culprit for stenosis in grafts, and thus prevent AV graft failure. This work will be accomplished in two aims:1) Production of affinity-based sirolimus releasing grafts; and 2) proof-of-concept in vivo validation of the anti-proliferative effect of th coated AV graft in a porcine iliac graft model. Affinity Therapeutics' proposed work is innovative; it represents the first AV graft capable of sustained, local drug delivery for preventing intimal hyperplasia. We use a novel approach to achieve high loading and long-term, sustained release of therapeutics well beyond that capable of other, diffusion-only systems studied. The expected outcomes include a coated AV graft capable of releasing sirolimus for 90 days that inhibits smooth muscle cell proliferation for 90 days in vivo. These results will positively impact the fiel of vascular access by providing an AV graft device for therapeutic delivery of antiproliferatives. Future work in Phase II will translate the Phase I proof-of-principle porcine in vivo studies into statistically powerful study to validate long-term graft patency. In addition, Affinity Therapeutic will continue to work with collaborators, including vascular surgeons and cardiologists to bring these coated vascular grafts closer to a clinical trial.

描述（由申请人提供）：有超过 160 万患者患有需要血液透析的终末期肾病。长期血管通路对于这些患者进行血液透析至关重要，可通过手术构建动静脉 (AV) 瘘或插入 AV 移植物来获得。血管通路失败导致这些患者的发病率甚至死亡率惊人。 AV 移植失败通常是由于 30% 的患者因吻合口狭窄而导致，需要进行手术翻修或通过血管成形术进行血管内再通。目前，尚无 AV 移植物可用于长期抗增殖治疗。我们的长期目标是生产可预防再狭窄并可用于血液透析而不会产生并发症的 AV 移植物。该提案的目的是评估基于亲和力的药物递送涂层，以实现西罗莫司的长期、持续递送。核心假设是，释放西罗莫司的涂层 AV 移植物将抑制平滑肌内膜生长（移植物狭窄的主要原因），从而防止 AV 移植物失败。这项工作将实现两个目标：1）生产基于亲和力的西罗莫司 释放移植物； 2) 在猪髂骨移植模型中对涂层 AV 移植物的抗增殖作用进行体内概念验证。 Affinity Therapeutics 提出的工作具有创新性； 它代表了第一个能够持续局部给药以预防内膜增生的 AV 移植物。我们使用一种新颖的方法来实现治疗药物的高负载和长期持续释放，远远超出其他研究的仅扩散系统的能力。预期结果包括涂层 AV 移植物能够在 90 天内释放西罗莫司，从而在体内抑制平滑肌细胞增殖 90 天。这些结果将通过提供用于抗增殖药物治疗性输送的 AV 移植装置，对血管通路领域产生积极影响。第二阶段的未来工作将把第一阶段的猪体内原理验证研究转化为具有统计学意义的研究，以验证长期移植物通畅。此外，Affinity Therapeutic 将继续与血管外科医生和心脏病专家等合作者合作，使这些涂层血管移植物更接近临床试验。