Preeclampsia is a major complication of pregnancy. Responsible for thousands of maternal and fetal deaths, there is no treatment to arrest disease progression, except delivery. Therefore, a therapeutic could substantially improve fetal and maternal outcomes.
The preeclamptic placenta releases the anti-angiogenic factors soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) into the maternal circulation, causing endothelial dysfunction and organ injury. Also, preeclampsia is strongly associated with oxidative stress. Therefore, an ideal candidate therapeutic would be a drug that is safe in pregnancy and can do the following: 1) decrease sFlt-1 and sEng secretion 2) block endothelial dysfunction 3) up-regulate endogenous anti-oxidant defences and 4) is effective in an animal model of preeclampsia.
Over two years, our team has developed a preclinical screening pipeline to identify drugs that are safe in pregnancy and have these important biological actions. Importantly, we only use primary human tissues.
For example, we have found proton pump inhibitors (e.g. esomeprazole, they are commonly used to treat gastric reflux that occurs during pregnancy) are a candidate treatment. They have potent effects in 1) decreasing sFlt/sEng expression and secretion from 4 different primary tissues (primary trophoblast, preeclamptic placental explants, two endothelial cell types), 2) blocking endothelial dysfunction (five different assays, including whole vessel pressure myography) and 3) up-regulating anti-oxidant defences. Furthermore, proton pump inhibitors 4) ameliorate the preeclamptic phenotype in an animal model where sFlt-1 is over-expressed in the placenta. Consequently, we have moved this concept into a phase II randomised clinical trial, about to commence in South Africa.
Using this approach to screen for candidate therapeutics for preeclampsia, we have validated the premise that pravastatin may be a treatment. In addition, we identified other exciting candidate treatments, including metformin, solfacone, YC-1, sulfasalazine, and even epidermal growth factor.