Research Project
8813639
DESCRIPTION (provided by applicant): Preeclampsia is a pregnancy-specific, hypertensive disorder that 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. It is generally agreed that the best approach to prevent adverse preeclampsia-associated complications 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 to be clearly defined, preeclampsia has been proposed to involve an altered balance between pro- and anti-angiogenic factors, dysregulated immune response to the allogenic fetus, incomplete trophoblast invasion and remodeling of spiral arteries, or a combination of impaired oxygen supply and placental oxidative stress. These defects could lead to restricted maternal-fetal blood circulation and systemic endothelial dysfunction, leading to high blood pressure, proteinuria, and fetal growth restriction. Recent studies have shown that signaling of CLR/RAMP receptors plays critical roles in the development of feto-placental tissues, and vasotone regulation during pregnancy. Importantly, it has been shown that blocking of CLR/RAMP receptor signaling leads to preeclampsia-like symptoms in pregnant animals. On the other hand, the activation of CLR/RAMP receptors can dampen preeclampsia-like symptoms in animals that have been pretreated with a nitric-oxide-synthase inhibitor or a CLR/RAMP receptor antagonist. Therefore, pharmacological activation of CLR/RAMP receptors could be a promising approach for treating hypertension, proteinuria, and fetal growth restriction in preeclampsia patients. Our goal is to develop a hormonal therapy based on stable CLR/RAMP receptor agonists that we recently developed. This therapy is expected to have potent efficacy in reducing blood pressure, edema, proteinuria, and fetal growth restriction in preeclampsia patients, thereby reducing preterm birth resulting from preeclampsia. Successful demonstration of the efficacy of lead compounds would validate our drug candidates, and facilitate the preclinical development of these therapeutic candidates in the Phase II STTR investigation.
