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. 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 (particularly sFlt1) and 3) endothelial dysfunction.
Methods: We have developed a preclinical screening approach utilising primary human tissues and a mouse model of preeclampsia to test therapeutic candidates for preeclampsia. In our models we have been 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.
Results: We have exciting preclinical data demonstrating new generation antiplatelet agents induce cytoprotective antioxidant pathways, reduce oxidative stress, potently reduce sFlt1 and pro-inflammatory cytokine secretion by human cytotrophoblast and preeclamptic placental tissue, rescue endothelial dysfunction and induce vascular relaxation.
Using a nanoparticle coated with the epidermal growth factor receptor (EGFR) to deliver siRNA directly to the placenta, we have demonstrated the nanoparticles can 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.
Conclusion: 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.