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

点击翻译按钮获取中文摘要

Abstract Summary 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 rates 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 will 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 the 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 field 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 a statistically powerful study to validate long-term graft patency. In addition, Affinity Therapeutics will continue to work with collaborators, including vascular surgeons and cardiologists to bring these coated vascular grafts closer to a clinical trial.