Novel Pharmacological Treatment for Preeclampsia 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.
Public Health Relevance Statement: Narrative Preeclampsia (preE) is a complication of pregnancy that affects 5-10% of pregnancies and can be life- threatening. PreE patients are given supportive therapy, such as anti-hypertensives and steroids. No specific and effective therapy, other than delivery, exists. Recently, the peptide hormone relaxin has been shown effective in small animal models and safety in human patients. We have identified a novel relaxin analog that will be the first effective treatment of preE.
Project Terms: Acetates; 3'5'-cyclic ester of AMP; Adenosine Cyclic 3',5'-Monophosphate; Adenosine Cyclic Monophosphate; Adenosine, cyclic 3',5'-(hydrogen phosphate); adenosine 3'5' monophosphate; cAMP; Cyclic AMP; Affect; aminoacid; Amino Acids; Animals; Anti-Hypertensive Agents; Anti-Hypertensive Drugs; Anti-Hypertensives; Antihypertensive Agents; Antihypertensive Drugs; Antihypertensives; Hypotensive Agent; Hypotensive Drugs; anti-hypertension; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Birth Weight; Blood Pressure; Cell Survival; Cell Viability; Cells; Cell Body; Clinical Trials; Cross Reactions; Cessation of life; Death; Deoxycorticosterone; 11-Decorticosterone; 21-Hydroxyprogesterone; Cortexone; Desoxycorticosterone; Desoxycortone; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Edema; Dropsy; Hydrops; Family; Fetus; Fibroblasts; Fibrosis; Goals; Half-Life; Heart failure; cardiac failure; hemodynamics; Human; Modern Man; Hypertension; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; high blood pressure; hyperpiesia; hyperpiesis; hypertensive disease; hypertensive disorder; Infant; Ischemia; Ligands; Long-Term Effects; Longterm Effects; Magnesium; Mg element; Morbidity - disease rate; Morbidity; mortality; Mothers; Parents; parent; Patients; Peptides; Perfusion; Drug Kinetics; Pharmacokinetics; Pre-Eclampsia; EPH Gestosis; Preeclampsia; Pregnancy Toxemias; Proteinuria-Edema-Hypertension Gestosis; pre-eclamptic; pregnancy toxemia/hypertension; Pregnancy; Gestation; Pregnancy Complications; complications during pregnancy; pregnancy-related complications; pressure; Proteinuria; Rattus; Common Rat Strains; Rat; Rats Mammals; Relaxin; Safety; Seizures; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Specificity; Steroids; Steroid Compound; Syndrome; Testing; Time; Toxicology; United States Food and Drug Administration; Food and Drug Administration; USFDA; Uterus; womb; Vasodilation; Vasodilatation; Vasorelaxation; Work; relaxin receptor; Measures; Encephalopathies; Hepatic Failure; Liver Failure; Mediating; medical costs; Medical Care Costs; Prematurely delivering; Preterm Birth; premature childbirth; premature delivery; preterm delivery; Premature Birth; pregnancy disorder; improved; Acute; Clinical; Phase; Variation; Variant; biologic; Biological; Physiologic; Physiological; Peptide Receptor; analog; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Supportive care; Supportive Therapy; Life; Complex; Continuous Infusion; System; fetal; Cytoprotection; Cell Protection; cytoprotective; infant death; death in first year of life; infant demise; infantile death; disulfide bond; peptide hormone; Peptide Hormone Gene; receptor; Receptor Protein; Animal Model; Animal Models and Related Studies; model of animal; Toxic effect; Toxicities; novel; G-Protein-Coupled Receptors; G Protein-Complex Receptor; G Protein-Coupled Receptor Genes; GPCR; Pharmacodynamics; Modeling; Property; response; assay development; palliative; small molecule; Address; Dose; Data; Receptor Signaling; in vivo; Pharmacological Treatment; Preparation; preparations; Molecular; pre-clinical; preclinical; preclinical study; pre-clinical study; neonate; innovate; innovative; innovation; therapeutic target; pregnant; effective treatment; effective therapy; in vitro activity; Peptide-based drug; therapeutic peptide; peptide drug; improved outcome; RXFP2; relaxin/insulin-like family peptide receptor 2; RXFP2 gene; cardioprotectant; cardioprotective; cardioprotection; animal safety; insulin-like peptide; hypertensive; manufacture
