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

DESCRIPTION provided by applicant There are greater than 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 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 Production of affinity based sirolimus releasing grafts and proof of concept in vivo validation of the anti proliferative effect of th coated AV graft in a porcine iliac graft model Affinity Therapeuticsandapos 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 days that inhibits smooth muscle cell proliferation for 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 PUBLIC HEALTH RELEVANCE This proposal is critically concerned with the issue of public health in that its long term goal is to provide a surgical vascular graft for arteriovenous interposition such as is used in hemodialysis that is free from restenosis Specifically we hope to accomplish this goal using an affinity based drug delivery system The short term goals are to develop a graft coating from affinity based polymers and to assess the efficacy of sirolimus delivery in a porcine iliac graft in vivo model