Novel GPCR-targeted therapy for preeclampsia

Novel GPCR targeted therapy for preeclampsia AbstractPreeclampsiapreEis a serious complication of pregnancy manifested by high blood pressureproteinuriaand edemasometimes with encephalopathyseizuresand hepatic failurePreE complicatestoof pregnanciesand is a major cause of maternal and fetal morbidity and mortality worldwideNeverthelessan effective therapy for this disorder does not existThere is no known specific treatmentalthough palliative measures such as antihypertensive drugsmagnesiumand steroidsand early delivery improve outcomesHrelaxinserelaxinacts on the G protein coupled receptorGPCRRelaxin Family Peptide ReceptorRXFPto mediate vasodilatory and cardioprotective effects in patients with acute heart failureAHFHoweverthe long term beneficial effects of serelaxin in AHF are likely related to its strong antifibrotic effects that have been shown in multiple animal modelsRecent data suggest that serelaxin may be a promising treatment for preEDespite its enormous promiseserelaxin has a short half life in vivois difficult to synthesizeand cross reacts with the related receptorRXFPIn additionthe cAMP mediated actions of serelaxin may be associated with deleterious long term effectsTo address these limitationswe have identified a novel B chain only peptide variant of serelaxinBwhich is RXFPspecificameliorates fibrosis via cell specific effects on fibroblastsis less expensive to manufactureand as a single chain peptide is also far easier to functionalize to improve its stability and in vivo efficacyBis the first single chain insulin like peptide having a selective signaling profile that favors the anti fibrotic actions of serelaxinbut with minimal cAMP related effectsThe overall goal of this project is to develop and characterize Bas an innovative treatment for preEIn Phasewe will construct an Fc fusion of Bto increase its plasma halflifeWe will confirm biological activity in vitro and evaluate BFc in a cytotrophoblast assay and in a small animal model of preEProduction of BFc with similar activity as the parent Band ability to normalize expression of angiogenic factorswill merit submission of a PhaseapplicationPhasework will focus on obtaining the preclinical data necessary for submission of an INDPharmacokinetics and toxicity studiesas well as animal studies to demonstrate efficacywill be performed NarrativePreeclampsiapreEis a complication of pregnancy that affectsof pregnancies and can be lifethreateningPreE patients are given supportive therapysuch as anti hypertensives and steroidsNo specific and effective therapyother than deliveryexistsRecentlythe peptide hormone relaxin has been shown effective in small animal models and safety in human patientsWe have identified a novel relaxin analog that will be the first effective treatment of preE