A holy grail for pre-eclampsia research is to discover a magic bullet that quenches the disease. Such a wonder drug could buy time for clinicians to safely deliver women affected by severe disease and minimise organ injury. Quite possibly, those with preterm pre-eclampsia could be given such a drug and be safely coasted along to a more advanced gestation, removing the fetus from the perils of severe prematurity. Sadly, no such treatment exists. And arguably, there are very few new serious contenders touted that are close to clinical trials.

Will a treatment be found? Of course we don’t know, but over the past two years our team – The Translational Obstetrics Group (Mercy Hospital, University of Melbourne) – has set up a preclinical screening pipeline so we can go hunting for a treatment.

Our team believes an ideal therapeutic candidate is one that can block key steps in the pathology of pre-eclampsia. It should potently decrease sFlt-1 and soluble endoglin secretion. But ideally, it should do more, such as mobilise the body’s endogenous anti-oxidant defences and block endothelial dysfunction. Our system rigorously tests whether the drugs we screen can do some, or all these things.

Importantly, we exclusively use primary human tissues. This does inflict the drudgery of a six-hour isolation step for primary trophoblast studies. However, we have far more faith in our findings using primary tissues in place of BeWos, JEGs, and other cell lines. Bizarrely, pretty much none of the placental cell lines secrete sFlt-1 or soluble Endoglin (BeWos can be persuaded to secrete alittle if you syncytialise them). BeWos reportedly contain a crazy number of chromosomes (>60-70+) that any self-respecting non-malignant cell just shouldn’t have.

To screen whether drugs decrease sFlt-1 and soluble endoglin secretion, we add them to placental and endothelial cells, their two main tissue sources. And we test four primary tissues: purified primary trophoblast, placental explants from women with severe preeclampsia and two primary endothelial cell types.

We are believers that endothelial dysfunction is an absolutely critical step in pre-eclampsia. Thus, our interrogation to examine whether drugs can block endothelial dysfunction is particularly comprehensive. We examine whether drugs can block endothelial expression of either VCAM-1 or endothelin-1 (molecular markers of endothelial dysfunction). We also perform leukocyte adhesion assays and we examine whether drugs can enhance endothelial cell proliferation and migration (using the xCELLigence system, which monitors experiments in real time). We interrogate two primary endothelial cell types using these assays. Also, we incite endothelial dysfunction using two models: we add either TNFα, or serum obtained from women with severe preeclampsia.

Our last test of endothelial dysfunction is particularly exciting for us. We harvest whole blood vessels from the omentum at caesarean section from women with severe preterm preeclampsia. My vascular biology collaborator (A/Prof Laura Parry, Uni of Melbourne) then performs pressure myography to see whether the drugs can vasodilate these diseased maternal vessels.

Finally, we test drugs in two complementary animal models.

Using these assays, we are starting to identify some exciting new candidate treatments. Our lead candidate is – rather unexpectedly – proton pump inhibitors. We clinicians prescribe them all the time to pregnant women troubled by gastric reflux, caused by the pressure of the gravid belly.

We have found proton pump inhibitors potently decrease sFlt-1/sEng production, up-regulate anti-oxidant defences and quench endothelial dysfunction. They also seem to work in our animal models. We have set out to translate this work with The PIE Trial (Pre-eclampsia intervention with esomeprazole), set to begin this year. In the PIE trial, we will randomise 120 women with severe preterm preeclampsia to either esomeprazole or placebo. We proudly note that PIE, fully funded by philanthropic donations, will be based in South Africa. This is a country where rates of pre-eclampsia and eclampsia remain depressingly high.

We have not stopped with proton pump inhibitors. We have now identified a cache of drugs with the magical combined properties of dropping sFlt-1/soluble endoglin secretion, reducing endothelial dysfunction and switching on anti-oxidant defences. We presented data at ISSHP to show sulfasalazine (anti-inflammatory drug that can be given to pregnant women) can do it. Noting that the preclinical evidence for pravastatin as a possible treatment was generated in animal models, we tested pravastatin using primary human tissues and found that it also performs well. There are a slew of other drugs that also look promising that we cannot wait to reveal. One seems particularly potent and just might also rescue the fetal growth restriction that so often complicates preeclampsia.

Over recent decades a lot of the fundamental biology underlying pre-eclampsia has been elegantly unravelled. To my mind, the field still has work to do on molecular mechanisms in the pre-eclamptic placenta, but we have probably identified the key steps in the pathogenesis. It is on the back of these amazing discoveries by giants in the field (many of whom are still members of ISSHP) that we have been able to come up with a sensible strategy to hunt for treatments for pre-eclampsia. We are hoping that our collective efforts just might nail the magic bullet to alleviate the oppressive global burden caused by pre-eclampsia.

Professor Stephen Tong

Head, Translational Obstetrics Group
University of Melbourne, Mercy Hospital for Women.