Development of a targeted therapeutic to prevent preeclampsia.

Asif Ahmed1,2, Homira Rezai 1, Milda Grubliauskiene1, Shakil Ahmad1,3, Keqing Wang1,3

1Mirzyme Therapeutics, Innovation Birmingham Campus, Faraday Wharf, Holt Street, Birmingham B7 4BB, United Kingdom; 2School of Health Sciences, University of Southampton, Southampton, SO17 1BJ, UK; 3Aston Medical Research Institute, Aston Medical School, Birmingham, United Kingdom

Every minute a life is lost due to preeclampsia. It affects 1 in 12 of the 131 million pregnancies a year. There are no approved therapeutics to prevent or treat preeclampsia and the annual global cost burden is over 100 billion US dollars. Preeclampsia is a risk factor for cardiovascular disease, stroke and vascular dementia in later life. Ahmed’s laboratory demonstrated that preeclampsia is caused by high soluble fms-like tyrosine kinase 1 (sFlt-1) and low heme oxygenase-1 (HO1 / Hmox1) expression. HO-1 and microRNAs that regulate target gene expression post-transcriptionally hold the key to the pathophysiology of preeclampsia. Bioinformatics analysis and luciferase assay confirmed that specific microRNAs directly targets 3’-UTR of sFlt-1 mRNA to limit sFlt-1 release. Levels of these microRNAs were decreased in the placenta of the mouse model of preeclampsia and in women with preeclampsia, supporting their role in vivo. Using molecular studies, transgenic mouse models and clinical studies, we investigated the role of this protective pathway. We sought to determine the therapeutic value of a novel H2S-releasing aspirin (MZe786) in HO-1 haploid deficient (Hmox1+/-) pregnant mice in a high sFlt-1 environment. Pregnant Hmox1+/- mice were injected with adenovirus (Ad) encoding sFlt-1 or CMV (control virus) at gestation day E11.5. Subsequently, Hmox1+/- dams were treated daily with a number of treatment regimens until E17.5, when maternal and fetal outcomes were assessed. We showed that HO-1 compromised pregnant mice in a high sFlt-1 environment exhibit severe preeclampsia signs and a reduction in antioxidant genes. MZe786 ameliorated preeclampsia by reducing hypertension and renal damage by stimulating antioxidant genes and improving fetal outcome in comparison with aspirin alone. MZe786 is a better therapeutic agent at preventing preeclampsia than aspirin alone.