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 novel agents targeting each of these pathways, a supplementary VEGF therapy to counteract the increased sFlt-1 levels and NF-κB 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. During the first funding period, we assessed the therapeutic potential of one agent from each class, ELP fusion to VEGF-A121 to counteract sFlt-1 and an ELP fusion to a peptide that blocks NF-kB nuclear import to counteract the inflammatory signaling. We confirmed the activity of both agents in vitro, measured their in vivo pharmacokinetics and confirmed that ELP fusion prevents their placental transfer, and demonstrated their therapeutic efficacy in a rat model of preeclampsia. While both agents were effective in the rat model, we believe that each may be improved. For the ELP-fused VEGF, we hypothesize that a different, less angiogenic form of VEGF (VEGF-B167), will have more potent sFlt-1 binding while inducing less aberrant angiogenesis, thus making it a safer therapeutic option. For the NF-kB inhibitory peptides, we have generated five new peptides that target the NF-kB activation cascade a different levels, and we hypothesize that one (or a combination of multiple) of these peptides will have a more potent anti- inflammatory effect. During the renewal period, we will evaluate our second-generation agents in vitro to confirm their target binding and mechanism of action, assess their safety, pharmacokinetics, and therapeutic efficacy in our rat model of placental ischemia, and, in order to advance our lead agents toward translation, assess their safety and efficacy in a novel non-human primate model of gestational hypertension, the African Green Monkey.