A Novel Protein Delivery System for Therapy of Preeclampsia

描述(申请人提供)：先兆子痫是一种常见的妊娠高血压疾病，是导致孕产妇、胎儿和围产儿发病率和死亡率的主要原因之一。在美国，大约8%的孕妇会受到子痫前期的影响，表现为典型的高血压、蛋白尿和心血管功能改变，如果不加以控制，可能会导致产妇癫痫发作和死亡。除了引产外，目前尚无有效的干预措施来治疗先兆子痫，这就是为什么它也是早产的主要原因。由于各种拟议的小分子疗法对发育中的胎儿的有害影响，先兆子痫治疗的改善在很大程度上被扼杀了。拟议研究的目的是开发一种药物输送系统，该系统能够稳定母体循环中的新型治疗剂，同时保护它们不进入胎儿循环。先兆子痫的发生和发展由两条主要途径驱动，一条是分泌血管内皮生长因子拮抗剂sFlt-1，另一条是在母亲体内诱导高度炎症环境。我们已经开发了两种针对每种途径的新药物，一种是补充的血管内皮生长因子疗法，以对抗sFlt-1水平的升高，另一种是核因子-kB抑制肽疗法，用于阻断炎症反应。这些疗法附着在一种名为弹性蛋白样多肽(ELP)的药物输送载体上，该载体可以稳定它们在母体循环中的作用，同时防止它们穿过胎盘进入胎儿循环。该方案的目的是：1)评价该药物载体的药代动力学、生物分布、胎盘靶向性和胎儿排斥性；2)评价ELP-VEGF治疗大鼠先兆子痫的体外机制和体内疗效；3)评价ELP融合的体外机制和体内疗效。 在大鼠先兆子痫模型中进行核因子-κB抑制治疗，以及4)评估使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.