Novel therapy for preeclampsia

先兆子痫的新疗法

• 批准号: 10480975
• 负责人: Mohammad Nasir Uddin
• 金额: $ 38.5万
• 依托单位: EMERGENT BIOTECHNOLOGIES LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480975
• 关键词: Active Sites; Affect; Angiogenic Factor; Angiotensin I; Angiotensinogen; Animal Model; Animals; Antibodies; Antihypertensive Agents; Attenuated; Binding; Biological; Biological Assay; Blood flow; Chimeric Proteins; Clinical; Data; Diabetic Nephropathy; Diabetic Retinopathy; Disease; Drug Kinetics; Edema; Encephalopathies; Event; Fc Immunoglobulins; Goals; Half-Life; Human; Hypertension; In Vitro; Inactive Renin; Left; Letters; Life; Liver Failure; Magnesium; Measures; Modeling; Morbidity - disease rate; Nutrient; Outcome; Oxygen; Parents; Pathogenesis; Pathologic; Patients; Peptides; Peptidyl-Dipeptidase A; Perfusion; Pharmaceutical Preparations; Phase; Physiological; Placenta; Plasma; Play; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Proteinuria; Rattus; Regulation; Renin; Renin-Angiotensin System; Role; Seizures; Signal Pathway; Signal Transduction; Source; Steroids; Supportive care; Therapeutic Intervention; Time; Toxic effect; Up-Regulation; Vascular remodeling; Vascular resistance; Work; angiogenesis; base; cytotrophoblast; effective therapy; experimental study; fetal; improved; improved outcome; in vitro activity; in vivo; in vivo Model; innovation; interest; maternal serum; mortality; new therapeutic target; novel; novel therapeutics; palliative; pre-clinical; prevent; prorenin receptor; protein aminoacid sequence; receptor; therapeutically effective; vasoconstriction

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.

先兆子痫的新疗法 摘要 先兆子痫（preE）是一种严重的妊娠并发症，表现为高血压、蛋白尿， 和水肿，有时伴有脑病、癫痫和肝功能衰竭。PreE使5%至10%的 这是导致孕妇怀孕的主要原因，也是全世界孕产妇和胎儿发病和死亡的主要原因。然而，一个 对这种疾病没有有效的治疗方法。没有已知的具体治疗方法，虽然姑息 抗高血压药物、镁和类固醇等措施以及早期分娩可改善结局。一 越来越多的证据支持存在局部的、内在活性的肾素-血管紧张素系统（RAS） 参与调节蜕膜血管重塑和子宫胎盘血流。一些间接 一系列证据表明，胎盘中RAS的上调在preE的发病机制中是重要的。 （Pro）肾素可以在体内通过蛋白水解和非蛋白水解被激活。受体上的“手柄”区域 在（原）肾素与（P）RR结合及其非蛋白水解激活中起重要作用。基于以下的十肽 该β-区序列（β-区肽或HRP）可阻断（原）肾素与（P）RR的结合。我们 假设用这种诱饵肽阻断可以有效地改善局部胎盘灌注并延长 妊娠的持续时间，一个重要的临床结果。最近，高循环水平的可溶性（P）RR被认为是 在preE患者分娩时检测到，发现血浆和胎盘（原）肾素升高， 在preE和preE大鼠模型中。该项目的总体目标是开发和表征HRP， 一种治疗前E的创新疗法在第1阶段，我们将使用以下标记物在体外确认生物活性： 在细胞滋养层（CTB）测定中的血管生成。我们将评估这种肽的HRP和延长半衰期形式 这是第一次在preE的动物模型中。证明了使血管生成因子表达正常化的能力。 CTB试验中的因素和动物模型中的活性，将值得提交2期申请。相 2项工作将侧重于获得提交IND所需的临床前数据。药代动力学和 将进行毒性研究以及动物研究以证明功效。