Abstract
Objectives There are currently no effective interventions for preeclampsia short of induced delivery of the fetus. Improvements in preeclampsia management have been stifled due to deleterious effects of proposed small-molecule drugs on the fetus. Our overall goal is to generate novel, maternally sequestered therapeutics for preeclampsia. The progression of preeclampsia is driven by three major pathways, secretion of the VEGF antagonist sFlt-1 by the hypoxic placenta, induction of an inflammatory environment in the mother, and production of reactive oxygen species in the hypoxic placenta. We have generated novel biologics to target each of these pathways. Furthermore, these therapeutics are attached to a drug delivery vector called elastin-like polypeptide (ELP) that stabilizes them from rapid clearance and degradation in the maternal circulation while preventing them from crossing the placenta into the fetal circulation. Methods Biodistribution of ELP-fused therapeutics in pregnant rats was determined by ex vivo whole-organ fluorescence and quantitative fluorescence histology. Efficacy for reducing the maternal symptoms and improving markers of fetal health was assessed in a rat model of placental insufficiency. Results In vitro studies validated that each of these therapeutics are active against their desired target. The ELP carriers deposited at high levels in the placenta, but did not cross into the fetal circulation, even after continuous infusion for 5 days. In addition, attachment a therapeutic peptide to ELP increased its plasma half-life from minutes to hours, and placental levels of the ELP-delivered peptide were 35-fold higher than levels of the free peptide. Ongoing studies are evaluating the efficacy of each of these novel therapeutics for prevention of preeclampsia-like symptoms and improved markers of fetal health. Conclusions Our results have established ELP as a promising drug carrier for maternally sequestered therapy, and these novel agents have the potential to be useful new classes of therapeutics for preeclampsia. Disclosures G.L. Bidwell Commercial Interest: Owner and Manager, Leflore Technologies LLC. E.M. George: None.
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