mRNA lipid nanoparticles for pre-eclampsia

PROJECT SUMMARY Pre-eclampsia is an obstetric condition that affects 5–8% of all pregnancies and is a leading cause of maternal mortality worldwide. Pre-eclampsia is characterized by the onset of maternal hypertension after 20 weeks of gestation, stemming from insufficient remodeling of the uterine spiral arteries that supply blood flow to the placenta and fetus. Clinical treatments for pre-eclampsia, such as antihypertensive drugs to manage blood pressure and anticonvulsants to prevent seizures, address the associated symptoms, yet no drug or therapeutic has been developed to slow the progression of pre-eclampsia. The only curative treatment option for pre- eclampsia is the early delivery of the placenta and fetus, which often resolves maternal hypertension within a few days, but can cause fetal morbidity and mortality, especially in cases where fetal growth restriction occurs concurrently with pre-eclampsia. Therefore, a significant unmet need exists for novel therapeutic strategies that can facilitate vasodilation in the placenta during pre-eclampsia to resolve maternal hypertension and improve fetal health. With no drug available to slow disease progression, engineering ionizable lipid nanoparticles (LNPs) for extrahepatic mRNA delivery to the placenta is an attractive therapeutic platform to treat pre-eclampsia. The goal of the proposed work is to develop a targeted, placenta-tropic LNP platform for the delivery of mRNA cargo to the placenta to treat pre-eclampsia during pregnancy. First, high-throughput in vivo screening will be utilized to evaluate a large library of LNPs with novel ionizable lipid structures and excipient compositions for extrahepatic tropism to the placenta. Lead candidates from this high-throughput screen will be functionalized with active targeting motifs, namely placenta-specific antibodies, for selective delivery to trophoblasts and endothelial cells in vivo. Following enrichment analysis using next generation sequencing, LNPs demonstrating placental tropism will be functionalized with placental-specific antibodies to promote active targeting to key cell types in the placenta — trophoblasts and endothelial cells. In vitro, ex vivo, and in vivo expression of therapeutic mRNA cargos (VEGF, PlGF, and eNOS) encapsulated in LNPs will then be evaluated in primary human and mouse placentas. The lead mRNA LNP candidates will then be utilized to rescue maternal hypertension, fetal health, and immunophenotype in an induced model of severe, early onset pre-eclampsia in mice. The work proposed here is the first to evaluate the therapeutic efficacy of a pro-angiogenic mRNA LNPs for treating pre-eclampsia, a placental disorder during pregnancy for which currently no curative treatment options exist. Due to the modular nature of LNPs and the ability to readily swap mRNA cargoes, the platform developed through the completion of these studies can be used for treating not only pre-eclampsia, but also a wide range of placental disorders occurring during pregnancy.