A luminal vascular coating to reduce time to maturation and failures of AV-Fistulas for hemodialysis access

 描述(由申请人提供)：研究领域：本提案针对NIH、CDC、FDA和ACF的小型企业创新研究资助申请(家长SBIR[R43/R44])的PHS 2014-02综合征集。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)，在老龄化人口中的发病率不断上升。近400,000名终末期肾病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人群发病率的主要原因之一是血液透析血管通路功能障碍，占该人群住院总数的20%。血管获取占联邦医疗保险在ESRD计划上的支出的7.5%，每年总计超过1BB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，导致了巨大的未得到满足的临床需求。自体动静脉内瘘(AVF)是血液透析的首选方法，因为一旦内瘘完全成熟，其感染和血栓发生率较低。然而，在欧洲和美国，23%-46%的AVF存在早期失败或未能成熟的问题，导致一年后的主要通畅率仅为60%-65%。早期和晚期的失败都以血管狭窄为特征，而与所有AVF失败相关的经典组织学病变是新生内膜增生。虽然许多因素在动静脉瘘新生内膜增生的发生发展中起作用，但血管内皮层的损伤程度与新生内膜增生的程度直接相关。塞米克正在开发一种用于血管通路的新疗法，旨在解决在创建房室瘘时发生的损伤。这种局部的管腔血管涂层被称为DS-sily，它结合到暴露的胶原蛋白上，阻止血小板与血管壁的粘连，从而抑制血栓形成和新生内膜增生的启动事件。在这项研究的第一阶段，SYMIC显示，向新形成的瘘管输送双链淀粉显著增加了瘘管静脉的直径，达到生理盐水对照组的3倍。在这里，我们将把这些增大的直径与增大的流速相关联，以确认这些瘘管对于血液透析通路是适当成熟的。此外，工作包括适当的制造控制以及安全和毒理学研究，这是使DS-SIY进入早期临床工作所必需的。该项目的成功完成将导致一种新的治疗方法的临床开发，以减少血液透析患者血管通路失败的发生率。

 DESCRIPTION (provided by applicant): Research Area: This proposal addresses PHS 2014-02 Omnibus Solicitation of the NIH, CDC, FDA, and ACF for Small Business Innovation Research Grant Applications (Parent SBIR [R43/R44]). 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. Symic is develop 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 neointimal hyperplasia. In the Phase I portion of this work, Symic showed that delivery of DS-SILY to a newly formed fistula significantly increases the diameter of the fistula vein to 3 times the diameter of saline treated controls. Here we will correlate these increased diameters with increased flow rates to confirm that these fistulas are properly maturing for hemodialysis access. Additionally work includes the proper manufacturing controls and safety and toxicology studies necessary to move DS-SILY into early clinical work. Successful completion of this project will lead to the clinical development of a novel therapy to reduce the incidence of failure in vascular access for hemodialysis patients.