Preeclampsia is a serious complication of pregnancy. Responsible for over 60,000 maternal deaths worldwide and far greater rates of perinatal loss. There are currently no efficacious treatments to halt disease progression other than delivery. If preeclampsia onset is early in pregnancy, babies may need to be delivered preterm to save the mother. Thus a therapeutic that can quench disease severity would allow an extension of the pregnancy.
The key pathophysiological steps in preeclampsia include 1) placental damage and oxidative stress, 2) elevated anti-angiogenic factors (sFlt1 and sEng) and 3) endothelial dysfunction. Our team have developed a preclinical screening approach using primary human tissues and a novel mouse model of preeclampsia to test therapeutic candidates for preeclampsia.
Using our preclinical models, we identified proton pump inhibitors (PPIs) as a promising treatment for preeclampsia and are testing the PPI esomeprazole in a phase II randomised control trial. In these same models we are currently testing two novel approaches to prevent/treat preeclampsia: 1) ‘new generation’ antiplatelet agents as a medical therapy and 2) targeted silencing of placental sFlt1 via nanoparticle delivery of short interfering RNAs (siRNAs) directly to the placenta.
We have exciting preclinical data demonstrating new generation antiplatelet agents induce cytoprotective antioxidant pathways, potently reduce sFlt1/sEng secretion by human tissues and rescue endothelial dysfunction in our human models.
Using a nanoparticle coated with the epidermal growth factor receptor (EGFR) to deliver siRNA directly to the placenta, we have demonstrated the nanoparticles have excellent ability to silence human specific sFlt1 mRNA expression and protein secretion from human placental explants. Importantly these nanoparticles accumulate in the mouse placenta; we are currently testing their ability to rescue the preeclamptic phenotype in our mouse model of disease.
Preeclampsia is a significant complication of pregnancy. The novel strategies we are testing to prevent and or treat preeclampsia are focused toward clinical translation and offer exciting possibilities for the future management of preeclampsia. The findings have potential for major impact in the field and may benefit the health of women and babies at risk of preeclampsia.