Preeclampsia is a serious complication of pregnancy. Responsible for over 70,000 maternal deaths worldwide and far greater rates of perinatal loss. More recently the field has gained better understanding of the key pathological steps in preeclampsia, including placental oxidative stress, major imbalances in angiogenic factors and systemic maternal endothelial dysfunction. Despite this there has been minimal therapeutic advances over the past 50 years. A therapeutic that is safe in pregnancy that can quench disease severity is urgently needed.
We have developed a preclinical screening approach utilising primary human cells/tissues and a mouse model of preeclampsia to develop therapeutic candidates for the prevention and treatment of preeclampsia, and importantly to translate these discoveries into clinical trials.
Through this approach we have identified several drugs (safe to be taken in pregnancy) that have the unique ability to reduce oxidative stress, induce cytoprotective antioxidant pathways, potently improve the angiogenic imbalance, reduce the aberrant pro-inflammatory cytokine secretion in the placenta. Furthermore, these agents are able to rescue endothelial dysfunction, enhance vasodilation and reduce hypertension in our mouse model of preeclampsia. We have already begun translating these findings into a Phase II prevention and treatment trials.
We have also embarked on the development of a placental targeted delivery approach. Using nanoparticles targeted to placenta to deliver gene silencing RNA directly to the placenta, we have demonstrated these targeted nanoparticles can silence the major toxic anti-angiogenic factor, soluble fms-like tyrosine kinase 1 (sFlt1), in the human placenta. Importantly these nanoparticles accumulate in the mouse placenta; their ability to rescue the preeclamptic phenotype in our mouse model of disease is currently being assessed.
These novel strategies have demonstrated exciting potential for the prevention and/or treatment of preeclampsia, they are focused toward clinical translation and offer hope for improved management of preeclampsia.