A Novel Protein Delivery System for Therapy of Preeclampsia

描述（由申请人提供）：先兆子痫是一种常见的妊娠期高血压疾病，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，先兆子痫影响约8%的妊娠，表现为特征性高血压、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。目前没有有效的干预措施，先兆子痫短的胎儿引产，这就是为什么它也是早产的主要原因。由于各种提出的小分子治疗剂对发育中的胎儿的有害影响，先兆子痫管理的改善在很大程度上被扼杀。拟定研究的目的是开发一种药物递送系统，该系统能够稳定母体循环中的新型治疗药物，同时保护其不进入胎儿循环。先兆子痫的发作和进展由两个主要途径驱动，即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物，一种补充VEGF治疗以抵消增加的sFlt-1水平，一种NF-kB抑制肽治疗以阻断炎症反应。这些治疗剂附着在一种称为弹性蛋白样多肽（ELP）的药物递送载体上，该载体使它们在母体循环中稳定，同时防止它们穿过胎盘进入胎儿循环。该提议的目的是1）评估该药物载体的几次迭代的药代动力学、生物分布、胎盘靶向和胎儿排斥，2）评估ELP-VEGF治疗剂在大鼠先兆子痫模型中的体外机制和体内功效，3）评估ELP融合的VEGF治疗剂的体外机制和体内功效，4）评估ELP融合的VEGF治疗剂的体外机制和体内功效。 NF-κB抑制治疗在大鼠先兆子痫模型中的作用，和4）评估用这些测试试剂治疗的先兆子痫母亲的后代中高血压的发展。

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.