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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.

新型药物治疗先兆子痫