Novel Pharmacological Treatment for Preeclampsia

先兆子痫的新型药物治疗

• 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
• 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

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.

先兆子痫的新药物治疗 摘要 子痫前期是妊娠期高血压的一种严重并发症，常伴有蛋白尿 和水肿，有时伴有脑病、癫痫和肝功能衰竭。PreE使5%至10%的 怀孕，是全球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。H2 松弛素（serelaxin）作用于G蛋白偶联受体（GPCR），松弛素家族肽受体1（RXFP 1） 在急性心力衰竭（AHF）患者中介导血管扩张和心脏保护作用。然而，长期以来- serelaxin在AHF中的长期有益作用可能与其已显示的强抗纤维化作用有关 在多种动物模型中。最近的数据表明，serelaxin可能是一个有前途的治疗前E。尽管 serelaxin在体内的半衰期很短，很难合成，并且与 相关受体RXFP 2。此外，serelaxin的cAMP介导的作用可能与有害的 长期影响。为了解决这些局限性，我们已经鉴定了一种新的B链肽变体， serelaxin，B7-33，是RXFP 1特异性的，通过对成纤维细胞的细胞特异性作用来改善纤维化， 制造昂贵，并且作为单链肽也更容易官能化以提高其稳定性 和体内功效。B7-33是第一个具有选择性信号传导特征的单链胰岛素样肽， 有利于serelaxin的抗纤维化作用，但具有最小的cAMP相关作用。这个项目的总体目标是 项目是开发和表征B7-33作为preE的创新治疗。在第一阶段，我们将 在基于细胞的试验和小规模的试验中证明了B7-33的延长半衰期缀合物的生物活性， preE动物模型证明与母体B7-33相似的活性和减少preE综合征的能力 将值得提交第二阶段的申请。第二阶段的工作将集中在获得临床前 提交IND药代动力学和毒性研究以及动物研究所需的数据， 证明疗效，将进行。