A Luminal Vascular Coating to Prevent Intimal Hyperplasia Following Creation of a

描述（由申请人提供）：本提案涉及PHS 2012-02美国国立卫生研究院小企业技术转移资助申请的综合征集（母STTR [R41/R42]）。超过2000万美国成年人（十分之一）患有不同程度的慢性肾脏疾病（CDC），在老龄化人口中发病率不断上升。近40万ESRD患者接受某种形式的透析，绝大多数血液透析是在诊所进行的。ESRD人群发病的主要原因之一是血液透析血管通路功能障碍，占该人群所有住院治疗的20%。血管通路占医疗保险ESRD项目支出的7.5%，每年总计超过100亿美元。在过去的30年里，血液透析血管通路领域没有取得重大进展，导致巨大的临床需求未得到满足。原生动静脉瘘（AVF）是血液透析的首选方法，因为其感染和血栓形成率低，一旦瘘完全成熟。然而，在欧洲和美国，23-46%的AVF存在早期衰竭或未成熟的问题，导致1年的原发性通畅率仅为60-65%。早期和晚期的衰竭都以血管狭窄为特征，与所有AVF衰竭相关的典型组织学病变是新生内膜增生。虽然许多因素在AVF中新内膜增生的发展中起作用，但血管内皮层损伤的程度与发生的新内膜增生的程度直接相关。现在我们认识到，所有的血管操作都会对血管造成损伤，尤其是对腔内脆弱的内皮细胞。内皮的损伤暴露了血管中潜在的胶原蛋白。血小板很好地适应与胶原蛋白结合，在那里它们被激活并释放或上调许多血管活性物质和诱导凝血和炎症的因子。身体已经进化出这些反应，作为受伤后控制失血和对抗注射的有效手段；然而，在血管内发生的胶原蛋白引发的凝血和炎症反应是导致血栓形成和新生内膜增生的最初步骤。Symic正在开发一种用于血管通路的新型治疗方法，旨在解决在房室瘘形成过程中发生的损伤。局部管腔血管涂层，称为ds - siy，与暴露的胶原蛋白结合，阻断血小板粘附血管壁，从而抑制血栓形成和内膜增生的起始事件。Symic已经证明ds - sil在猪球囊血管成形术模型中成功地防止血小板粘附和内膜增生。在这里，我们将在一个具有良好特征的猪模型中测试ds - sil预防新生内膜增生的能力，该模型概括了人类AVF衰竭的发病机制。该项目的成功完成将导致一种潜在的新疗法，以减少血液透析患者血管通路失败的发生率

DESCRIPTION (provided by applicant): 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