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.

先兆子痫的新型药物治疗 抽象的 先兆子痫（preE）是一种严重的妊娠期高血压并发症，常伴有蛋白尿 和水肿，有时伴有脑病、癫痫发作和肝功能衰竭。 PreE 使 5% 到 10% 的问题复杂化 妊娠，是全世界孕产妇和胎儿发病和死亡的主要原因。尽管如此，一个 这种疾病不存在有效的治疗方法。尽管可以起到缓解作用，但尚无已知的具体治疗方法 抗高血压药物、镁和类固醇以及早期分娩等措施可以改善结局。氢2 松弛素 (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。然而，长期 Serelaxin 对 AHF 的长期有益作用可能与其已被证明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 可能是一种有前景的 preE 治疗方法。尽管 其巨大的前景，serelaxin 在体内半衰期短，难以合成，并且与 相关受体，RXFP2。此外，serelaxin 的 cAMP 介导的作用可能与有害的 长期影响。为了解决这些限制，我们发现了一种新的仅 B 链肽变体 serelaxin，B7-33 是 RXFP1 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，其作用较小 制造成本昂贵，并且作为单链肽也更容易功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谱的单链胰岛素样肽， 有利于 serelaxin 的抗纤维化作用，但与 cAMP 相关的作用最小。本次活动的总体目标 该项目旨在开发 B7-33 并对其进行表征，作为 preE 的创新治疗方法。在第一阶段，我们将 在基于细胞的测定和小规模实验中证明了 B7-33 的半衰期延长缀合物的生物活性 preE的动物模型。表现出与亲本 B7-33 相似的活性以及减少 preE 综合征的能力 模型中的内容值得提交第二阶段申请。第二阶段的工作重点是获得临床前 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，将被执行。