Novel 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. A growing body of evidence supports the existence of a local, intrinsically active renin-angiotensin system (RAS) that participates in the regulation of decidual vascular remodeling and uteroplacental blood flow. Several indirect lines of evidence indicate that upregulation of the RAS in the placenta is important in the pathogenesis of preE. (Pro)renin can be activated in vivo both proteolytically and nonproteolytically. A “handle” region on the receptor plays an important role in (pro)renin binding to (P)RR and its nonproteolytic activation. Decapeptides based on this handle-region sequence (handle-region peptides or HRP) can block binding of (pro)renin to (P)RR. We hypothesize that blockade with this decoy peptide may effectively improve local placental perfusion and extend the duration of pregnancy, an important clinical outcome. Recently, high circulating levels of soluble (P)RR were detected at delivery in patients with preE, and both plasma and placental (pro)renin were found to be elevated in preE and in a rat model of preE. The overall goal of this project is to develop and characterize HRP as an innovative treatment for preE. During Phase 1, we will confirm biological activity in vitro using markers of angiogenesis in a cytotrophoblast (CTB) assay. We will evaluate HRP and extended half-life forms of this peptide for the first time in animal models of preE. Demonstration of the ability to normalize expression of angiogenic factors in the CTB assay and activity in the animal model, 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.