Novel therapy for preeclampsia

先兆子痫的新治疗方法 摘要 子痫前期(Pree)是一种严重的妊娠并发症，表现为高血压、蛋白尿、 和浮肿，有时伴有脑病、癫痫发作和肝功能衰竭。Pree使5%至10%的 它是怀孕的主要原因，也是全世界孕产妇和胎儿发病率和死亡率的主要原因。然而，一个 这种疾病的有效治疗方法还不存在。目前还没有已知的特效治疗方法，尽管是姑息治疗。 降压药、镁和类固醇以及早产等措施可以改善结局。一个 越来越多的证据支持存在局部的、内在活跃的肾素-血管紧张素系统(RAS) 参与蜕膜血管重塑和子宫胎盘血流的调节。几个间接的 一系列证据表明胎盘中RAS的上调在Pree的发病机制中起重要作用。 (Pro)肾素可在体内被蛋白水解性和非蛋白水解性激活。受体上的“手柄”区域 在(PRO)肾素与(P)RR结合及其非蛋白水解性激活中起重要作用。基于十肽的 这个句柄区域序列(句柄区域多肽或HRP)可以阻断(Pro)肾素与(P)RR的结合。我们 推测用此诱饵多肽阻断可有效地改善局部胎盘血流灌注并延长 妊娠的持续时间，是一个重要的临床结局。最近，循环中高水平的可溶性(P)RR是 Pree患者分娩时检测到血浆和胎盘(PRO)肾素均升高 在普瑞和普瑞的大鼠模型中。该项目的总体目标是开发HRP并将其描述为 普瑞的创新疗法。在第一阶段，我们将使用标记物确认体外生物学活性 细胞滋养层细胞(CTB)中的血管生成实验。我们将评估该多肽的HRP和延长的半衰期形式 这是首次在普瑞的动物模型中发现。血管生成基因表达正常化能力的实验研究 CTB检测中的因素和动物模型中的活性，将值得提交第二阶段申请。阶段 2工作的重点将是获得提交IND所需的临床前数据。药动学和药动学 将进行毒性研究，以及证明疗效的动物实验。

Novel therapy for preeclampsia Abstract Preeclampsia (preE) is a serious complication of pregnancy manifested by high blood pressure, proteinuria, and edema, sometimes with encephalopathy, seizures, and hepatic failure. PreE complicates 5 to 10% of pregnancies and is a major cause of maternal and fetal morbidity and mortality worldwide. Nevertheless, an effective therapy for this disorder does not exist. There is no known specific treatment, although palliative measures such as antihypertensive drugs, magnesium, and steroids, and early delivery improve outcomes. A growing body of evidence supports the existence of a local, intrinsically active renin-angiotensin system (RAS) that participates in the regulation of decidual vascular remodeling and uteroplacental blood flow. Several indirect lines of evidence indicate that upregulation of the RAS in the placenta is important in the pathogenesis of preE. (Pro)renin can be activated in vivo both proteolytically and nonproteolytically. A “handle” region on the receptor plays an important role in (pro)renin binding to (P)RR and its nonproteolytic activation. Decapeptides based on this handle-region sequence (handle-region peptides or HRP) can block binding of (pro)renin to (P)RR. We hypothesize that blockade with this decoy peptide may effectively improve local placental perfusion and extend the duration of pregnancy, an important clinical outcome. Recently, high circulating levels of soluble (P)RR were detected at delivery in patients with preE, and both plasma and placental (pro)renin were found to be elevated in preE and in a rat model of preE. The overall goal of this project is to develop and characterize HRP as an innovative treatment for preE. During Phase 1, we will confirm biological activity in vitro using markers of angiogenesis in a cytotrophoblast (CTB) assay. We will evaluate HRP and extended half-life forms of this peptide for the first time in animal models of preE. Demonstration of the ability to normalize expression of angiogenic factors in the CTB assay and activity in the animal model, will merit submission of a Phase 2 application. Phase 2 work will focus on obtaining the preclinical data necessary for submission of an IND. Pharmacokinetics and toxicity studies, as well as animal studies to demonstrate efficacy, will be performed.