Project summary: Preeclampsia is a leading complication of pregnancy, causing significant perinatal mortality and morbidity. It remains a major medical challenge: its cause is still unclear, and there is no effective therapy. As a result, current standards of care are highly resource-intensive and largely reliant on pragmatic measures including assessment of known risk factors and close monitoring of blood pressure, urinary protein, ultrasound and the fetus. Once diagnosed, patients receive symptomatic treatment including anti-hypertensives and anti-convulsants, which do not address disease mechanisms or progression. Delivery, often premature, is the only ?cure?. Although a majority of preeclampsia complications occur in developing regions of the world, and there has been a steady decline of maternal mortality in most developed nations, maternal mortality in the United States has actually increased since 1990. A central problem is the lack of an effective, targeted therapy that addresses disease pathogenesis. The previous lack of understanding of the disease and safety concerns have hindered development of therapeutic agents, but recent discoveries have made this feasible. It is now understood that in women who are developing preeclampsia, the stressed placenta releases ?toxic, circulating? anti-angiogenic proteins into mother's blood, scavenging vascular growth factors and damaging the vasculature. Preclinical and clinical evidence indicates that it is feasible to reduce concentrations of anti-angiogenic proteins in the circulation, and thus to reduce the severity of preeclampsia. To translate this important knowledge into practical treatments, we have established relevant phenotypic trophoblast models and screened 360 approved clinical drugs that have favorable safety profiles in pregnancy. This pilot work has resulted in identification of promising drug candidates that show therapeutic potential for preeclampsia, reducing release of anti-angiogenic factors from the placenta. In the present work, we will further validate the efficacy, pharmacology, and pharmacokinetics of these agents in relevant trophoblast and animal models of preeclampsia, with the goal of developing translational pharmacodynamic-pharmacokinetic data bridging to known human dose exposures. We will also investigate the mechanisms underlying the new drug effects. At the end of this study, we will select one best candidate, that has the most favorable pharmacologic and safety profiles, for a future clinical trial in patients with severe preeclampsia. Our innovative repurposing strategy, by selecting clinical drugs with favorable safety features for pregnancy, circumvents the drawbacks of lengthy, costly, and high-risk conventional drug development, promising to translate important science into clinical use in an efficient way. The outcome of this work will immediately support a clinical trial in high-risk patients. If successful, we expect a fundamental impact on patient care, reducing the health and socioeconomic burdens globally.

R01HD096501

2018-08-22

2023-05-31