A Novel Protein Delivery System for Therapy of Preeclampsia

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Abstract. Preeclampsia is a common hypertensive disorder of pregnancy and is one of the leading causes of maternal, fetal, and perinatal morbidity and mortality. Affecting ~8% of all pregnancies in the US, preeclampsia displays characteristic hypertension, proteinuria, and altered cardiovascular function and, if left unchecked, can lead to maternal seizures and death. There is currently no effective intervention for preeclampsia short of induced delivery of the fetus, which is why it is also a leading cause of premature birth. Improvements in preeclampsia management have been largely stifled due to deleterious effects of various proposed small- molecule therapeutics on the developing fetus. The objective of the proposed studies is to develop a drug delivery system capable of stabilizing novel therapeutic agents in the maternal circulation while protecting them from entering the fetal circulation. The onset and progression of preeclampsia is driven by two major pathways, secretion of the VEGF antagonist sFlt-1 and induction of a highly inflammatory environment in the mother. We have developed two novel agents targeting each of these pathways, a supplementary VEGF therapy to counteract the increased sFlt-1 levels and an NF-¿B inhibitory peptide therapy to block the inflammatory response. These therapeutics are attached to a drug delivery vector called elastin-like polypeptide (ELP) that stabilizes them in the maternal circulation while preventing them from crossing the placenta into the fetal circulation. The aims of this proposal are to 1) assess the pharmacokinetics, biodistribution, placental targeting, and fetal exclusion of several iterations of this drug carrier, 2) evaluate the in vitro mechanisms and in vivo efficacy of the ELP-VEGF therapeutic in a rat preeclampsia model, 3) evaluate the in vitro mechanisms and in vivo efficacy of the ELP-fused NF-¿B inhibitory therapeutic in a rat preeclampsia model, and 4) assess the development of hypertension in the offspring of preeclamptic mothers treated with these test agents. !