A Novel Protein Delivery System for Therapy of Preeclampsia

描述（由申请人提供）：子痫前期是一种常见的妊娠高血压疾病，是孕产妇、胎儿和围产期发病率和死亡率的主要原因之一。在美国，约8%的孕妇患有先兆子痫，表现为特征性的高血压、蛋白尿和心血管功能改变，如果不加以控制，可导致产妇癫痫发作和死亡。目前还没有有效的干预措施对先兆子痫短引产胎儿，这就是为什么它也是早产的主要原因。由于各种小分子药物对发育中的胎儿的有害影响，子痫前期治疗的改善在很大程度上受到了抑制。拟议研究的目的是开发一种药物输送系统，能够在母体循环中稳定新型治疗剂，同时保护它们不进入胎儿循环。子痫前期的发生和发展是由两个主要途径驱动的，VEGF拮抗剂sFlt-1的分泌和母体中高度炎症环境的诱导。我们已经开发了两种针对这些途径的新药，一种是补充VEGF治疗，以抵消增加的sFlt-1水平，另一种是NF-kB抑制肽治疗，以阻断炎症反应。这些药物附着在一种叫做弹性蛋白样多肽（ELP）的药物传递载体上，在母体循环中稳定它们，同时防止它们穿过胎盘进入胎儿循环。本研究的目的是：1)评估该药物载体的药代动力学、生物分布、胎盘靶向性和多次迭代的胎儿排斥；2)评估ELP-VEGF在大鼠子痫前期模型中的体外机制和体内疗效；3)评估ELP-VEGF融合的体外机制和体内疗效

DESCRIPTION (provided by applicant): 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-kB 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, bio distribution, placental targeting, and fetal exclusion of several iterations f 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-κB 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.