Research Project
9618835
Novel GPCR-targeted therapy for preeclampsia Abstract Preeclampsia (preE) is a serious complication of pregnancy manifested by high blood pressure, 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 construct an Fc fusion of B7-33 to increase its plasma half- life. We will confirm biological activity in vitro and evaluate B7-33-Fc in a cytotrophoblast assay and in a small animal model of preE. Production of B7-33-Fc with similar activity as the parent B7-33 and ability to normalize expression of angiogenic factors, 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.
