This proposal addresses PHS 2012-02 Omnibus Solicitation of the NIH for Small Business Technology Transfer Grant Applications (Parent STTR [R41/R42]). More than 20 million American adults (1 in 10) have some level of chronic kidney disease (CDC), with a growing incidence in the aging population. Nearly 400,000 ESRD patients receive some form of dialysis, with the vast majority of hemodialysis being performed in a clinic. One of the major causes of morbidity for the ESRD population is hemodialysis vascular access dysfunction, which is responsible for 20% of all hospitalizations for this population. Vascular access accounts for 7.5% of Medicare's spending on the ESRD programs, a total of over $1BB per year. In the past 3 decades, there have been no major advances in the field of hemodialysis vascular access, resulting in a huge unmet clinical need. Native arteriovenous fistula (AVF) is the preferred method of access for hemodialysis because of its low rates of infection and thrombosis once the fistula has fully matured. However, between 23-46% of AVF in Europe and the US have problems with early failure or failure to mature, resulting in a primary patency of only 60-65% at 1 year. Both early and late failures are characterized by vascular stenosis, and the classical histological lesion associated with all AVF failure is neointimal hyperplasia. While many factors play a role in the development of neointimal hyperplasia in an AVF, the extent of damage to the endothelial layer of a vessel has been directly related to the degree of neointimal hyperplasia that occurs. It is now appreciated that all vascular manipulation results in damage to the vessel, particularly to the fragile endothelial cells lining the lumen. Damage to the endothelium exposes underlying collagen in the vessel. Platelets are well adapted to bind to collagen, where they become activated and release or upregulate numerous vasoactive agents and factors that induce coagulation and inflammation. The body has evolved these responses as an effective means for controlling blood loss and fighting injection following injury;however this same collagen initiated coagulation and inflammatory response occurring inside a vessel is the initial steps in the pathways that result in thrombosis and neointimal hyperplasia. Symic is developing a novel treatment for use in vascular access, aimed at addressing the injury that occurs in the creation of the AV fistula. The localized luminal vascular coating, called DS-SILY, binds to exposed collagen, blocking platelet adhesion to the vessel wall and thus inhibiting the initiating events in thrombosis and intimal hyperplasia. Symic has shown DS-SILY to be successful in preventing platelet adhesion and intimal hyperplasia in a porcine model of balloon angioplasty. Here we will test the ability of DS-SILY to prevent neointimal hyperplasia in a well-characterized porcine model that recapitulates the human pathogenesis of AVF failure. Successful completion of this project will lead to a potential novel therapy to reduce the incidence of failure in vascular access for hemodialysis patients

Public Health Relevance

Nearly 400,000 Americans are currently receiving hemodialysis for endstage renal disease. Vascular access dysfunction one of the highest causes of morbidity and highest costs for Medicare in this population. The proposed work aims to decrease failures of vascular access in hemodialysis by preventing neointimal hyperplasia

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1-DKUS-G (12))
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Moxey-Mims, Marva M
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Symic Biomedical, Inc.
San Francisco
United States
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Roy-Chaudhury, Prabir; Verma, Ashish (2015) Improving patient safety in vascular access: a role for individualization and patient preferences. Contrib Nephrol 184:136-42
Roy-Chaudhury, Prabir; Kruska, Lindsay (2015) Future directions for vascular access for hemodialysis. Semin Dial 28:107-13
Chan, Jenq-Shyong; Campos, Begoña; Wang, Yang et al. (2014) Proliferation patterns in a pig model of AV fistula stenosis: can we translate biology into novel therapies? Semin Dial 27:626-32