Novel Pharmacological Treatment for Preeclampsia

先兆子痫的新型药物治疗

基本信息

批准号：
10758980
负责人：
Babbette LaMarca
金额：
$ 38.53万
依托单位：
ARTEMIS BIOTECHNOLOGIES LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-05 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10758980
关键词：
Acetates Acute Address Affect Amino Acids Animal Model Animals Antihypertensive Agents Biological Biological Assay Biological Availability Birth Weight Blood Pressure Cell Survival Cells Cessation of life Clinical Clinical Trials Complex Continuous Infusion Cross Reactions Cyclic AMP Cytoprotection Data Deoxycorticosterone Disease Dose Drug Kinetics Edema Encephalopathies Family Fetus Fibroblasts Fibrosis Functional disorder G-Protein-Coupled Receptors Goals Half-Life Heart failure Human Hypertension Infant Ischemia Life Ligands Liver Failure Long-Term Effects Magnesium Measures Mediating Medical Care Costs Modeling Molecular Morbidity - disease rate Mothers Parents Patients Peptide Receptor Peptides Perfusion Pharmaceutical Preparations Pharmacodynamics Pharmacological Treatment Phase Physiological Pre-Eclampsia Pregnancy Pregnancy Complications Premature Birth Preparation Property Proteinuria RXFP2 gene Rattus Receptor Signaling Relaxin Safety Seizures Signal Transduction Specificity Steroids Supportive care Syndrome System Testing Time Toxic effect Toxicology United States Food and Drug Administration Uterus Variant Vasodilation Work analog animal safety assay development cardioprotection disulfide bond effective therapy fetal hemodynamics hypertensive improved improved outcome in vitro activity in vivo infant death innovation insulin-like peptide manufacture mortality neonate novel palliative peptide drug peptide hormone pre-clinical preclinical study pregnancy disorder pregnant pressure receptor relaxin receptor response small molecule therapeutic target

项目摘要

Novel Pharmacological Treatment for Preeclampsia Abstract Preeclampsia (preE) is a serious hypertensive complication of pregnancy often accompanied by 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. H2 relaxin (serelaxin) acts on the G protein-coupled receptor (GPCR), Relaxin Family Peptide Receptor 1 (RXFP1) to mediate vasodilatory and cardioprotective effects in patients with acute heart failure (AHF). However, the long- term beneficial effects of serelaxin in AHF are likely related to its strong anti-fibrotic effects that have been shown in multiple animal models. Recent data suggest that serelaxin may be a promising treatment for preE. Despite its enormous promise, serelaxin has a short half-life in vivo, is difficult to synthesize, and cross-reacts with the related receptor, RXFP2. In addition, the cAMP-mediated actions of serelaxin may be associated with deleterious long-term effects. To address these limitations, we have identified a novel B-chain-only peptide variant of serelaxin, B7-33, which is RXFP1-specific, ameliorates fibrosis via cell-specific effects on fibroblasts, is less expensive to manufacture, and as a single chain peptide is also far easier to functionalize to improve its stability and in vivo efficacy. B7-33 is the first single-chain insulin-like peptide having a selective signaling profile that favors the anti-fibrotic actions of serelaxin, but with minimal cAMP-related effects. The overall goal of this project is to develop and characterize B7-33 as an innovative treatment for preE. In Phase 1, we will demonstrate biological activity of an extended half-life conjugate of B7-33 in cell-based assays and in small animal models of preE. Demonstration of similar activity as the parent B7-33 and ability to reduce preE syndrome in the models 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.

子痫前期的新型药理治疗抽象的子痫前期（PREE）是严重的高血压并发症，通常伴有蛋白尿还有水肿，有时会出现脑病，癫痫发作和肝衰竭。 pree使5％至10％的复杂怀孕，是孕产妇和胎儿发病率和死亡率的主要原因。然而，一个对这种疾病的有效疗法不存在。虽然没有姑息治疗诸如降压药，镁和类固醇等措施以及早期递送改善了预后。 H2 松弛蛋白（Serelaxin）作用于G蛋白偶联受体（GPCR），松弛素家族肽受体1（RXFP1）介导急性心力衰竭（AHF）患者的血管舒张和心脏保护作用。但是，长期 Serelaxin在AHF中的术语有益作用可能与已显示的强抗纤维化作用有关在多个动物模型中。最近的数据表明，Serelaxin可能是PREE的一种有希望的治疗方法。尽管它的巨大诺言，Serelaxin在体内的半衰期短，很难合成，并且与相关受体RXFP2。此外，Serelaxin的CAMP介导的动作可能与有害长期影响。为了解决这些局限 Serelaxin，B7-33（RXFP1特异性），通过细胞特异性对成纤维细胞的影响改善纤维化，较少制造成本昂贵，并且作为单个链肽也更容易实现其稳定性和体内功效。 B7-33是第一个单链胰岛素样肽，具有选择性信号曲线，有利于Serelaxin的抗纤维化作用，但具有最小的与CAMP相关的作用。总体目标项目是为了开发和将B7-33作为Pree的创新治疗方法。在第1阶段，我们将展示了基于细胞的测定中B7-33的延长半衰期结合物的生物学活性动物模型。演示与父级B7-33相似的活性和减少pree综合征的能力在模型中，将值得提交2阶段应用程序。第2阶段的工作将重点放在获得临床前提交IND所需的数据。药代动力学和毒性研究，以及动物研究证明功效将进行。