Preeclampsia is a pregnancy-specific, hypertensive disorder that affects 5-8% of pregnancies. This disorder can lead to multi-organ failure, seizure, and maternal death. Preeclampsia is also responsible for as many as 20% of premature births in the United States. Although better neonatal care has improved the likelihood of preterm babies surviving, many face increased mortality and serious long-term morbidities. Medical experts agree that the best approach to prevent adverse preeclampsia-associated effects in babies is to delay premature birth. Unfortunately, current treatments are ineffective at delaying labor by more than a couple of days in the majority of preeclampsia patients. Although the cause of preeclampsia remains unclear, preeclampsia has been proposed to be a two-stage disease, which involves defects at the maternal-fetal interface as well as maternal vascular dysfunction. These defects could lead to systemic endothelial dysfunction. As a result, maternal-fetal blood circulation is restricted, leading to high blood pressure, proteinuria, and fetal growt retardation. Recent discoveries have shown that a group of vascular receptors, CLR/RAMP receptors, play crucial roles in the development of feto- placental tissues and vasotone regulation during pregnancy. Importantly, it has been shown that blocking CLR/RAMP receptor signaling leads to preeclampsia-like symptoms in animal models, and those agonists for CLR/RAMP receptors can dampen preeclampsia-like symptoms in animals that have been pretreated with a nitric-oxide-synthase inhibitor during late pregnancy. Therefore, pharmacological activation of CLR/RAMP receptor signaling could be a promising approach to treat hypertension, proteinuria, and fetal growth retardation in preeclampsia patients, and to reduce the likelihood of preterm birth. Our goal is to investigate the protective effects of a grou of novel CLR/RAMP receptor agonists, which have potent anti-hypertensive effects in vivo, in a preeclamptic rat model. Successful demonstration of the efficacy of these novel drug candidates would validate our lead compounds for further development, and facilitate the design of GLP pharmacokinetic and toxicology studies in the Phase 2 SBIR investigation.
Based on a group of human hormones that normally regulate vascular compliance during pregnancy, we have developed novel therapeutic candidates for the prevention of preterm births that result from preeclampsia. We will investigate the efficacy of these novel drug candidates using a preeclamptic rat model. The proposed study would validate our drug candidates for further preclinical development.