Proof of concept of new potential Therapeutic drugs to treat PreEclampsia – TheraPE

Preeclampsia (PE) is a hypertensive disorder of pregnancy related to a placentation defect. PE is a major cause of maternal and perinatal morbidity and mortality worldwide. Moreover, women who had PE and adults born preterm are at increased risk of cardiovascular diseases which are the leading cause of mortality in the world. Several clinical studies have demonstrated an increase (even before diagnosis) in arginine-vasopressin (AVP) and a decrease in Apelin circulating levels in PE, strongly suggesting that this hormonal AVP/Apelin imbalance may play significant role in the development of PE. Moreover, our preliminary data demonstrated the direct involvement of the activation of the type-2 AVP receptor, V2R, in the development of PE-like symptoms in rodents. Lastly, literature showed that Apelin preventive administration, by activating its receptor ApelinR, could reverse symptoms related to PE in rodents. Therefore, V2R-blocking and ApelinR-activation may represent a new therapeutic strategy for PE.
Unfortunately, due to the difficulty of using drugs during pregnancy, no cure exists for PE other than emergency child delivery, who is often preterm, affecting the baby’s survival and causing long-term health adverse effects. However, our consortium developed two novel compounds which do not cross the placental barrier, and therefore could be used during pregnancy. One compound blocks V2R and the other activates ApelinR. Both compound exhibit (sub)nanomolar affinity and high selectivity for their respective receptor.
Therefore, the two objectives of this project are 1st) to decipher the effect of these two compounds in vitro and ex vivo on human placentation, and 2nd) to evaluate the potential therapeutic impact of these two compounds to reverse PE features in rodents. For 1st objective purpose, we will evaluate the effects of compounds in vitro on human trophoblast cells and ex vivo on placental explants from PE women, following processes in the trophoblasts: i) proliferation, ii) migration, iii) apoptosis, and iv) differentiation. The secretome of these trophoblasts will be collected to analyze their production of inflammatory and angiogenic cytokines. Finally, we will lyse the trophoblasts to perform transcriptomic analysis. Results from this 1st objective expect to show that compounds have beneficial effects on human placentation with no toxicity. For 2nd objective purpose, we will investigate the effects of V2R-blocking and ApelinR-activation to reverse PE symptoms through a preventive and a curative chronic subcutaneous administration of compounds in PE rodent models. We will measure the main clinical features of PE, namely high blood pressure and proteinuria, over gestation. Before delivery, animals will be sacrificed to collect and weight tissues in order to perform immunohistochemistry analysis and to explore protein and/or gene expression of interest. Results from this 2nd objective expect to demonstrate the efficacy of compounds to reverse symptoms of PE in preclinical PE rodent models.
This project address the challenging medical need for pregnant women who develop PE by an original approach using compounds made in the consortium not crossing the placental barrier and targeting receptors playing major physiological role in this pathology.