A Novel Protein Delivery System for Therapy of Preeclampsia

抽象的。 子痫前期是一种常见的妊娠期高血压疾病，是导致孕妇、 胎儿、围产期发病率和死亡率。影响美国约8%的怀孕，先兆子痫表现为 特征性高血压、蛋白尿和心血管功能改变，如果不加以控制，可能会导致 产妇癫痫发作和死亡。目前还没有有效的干预措施来治疗先兆子痫 胎儿的分娩，这就是为什么它也是早产的主要原因。先兆子痫的改善 由于各种拟议的小分子疗法的有害影响，管理在很大程度上被扼杀了 在发育中的胎儿身上。拟议研究的目标是开发一种能够 稳定母体循环中的新型治疗药物，同时保护它们不进入胎儿 发行量。子痫前期的发生和发展由两条主要途径驱动，即分泌血管内皮生长因子 拮抗剂sFlt-1和在母亲体内诱导高度炎症环境。我们已经开发出了小说 针对每一条通路的药物，补充血管内皮生长因子治疗以抵消增加的sFlt-1 应用核因子-κB抑制性多肽治疗阻断炎症反应。这些治疗药物是附加的 一种名为弹性蛋白样多肽(ELP)的药物输送载体，它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。在第一个资助期内，我们评估了 每类药物中的一种ELP与VEGF-A121融合以对抗sFlt-1和ELP的治疗潜力 融合成一种多肽，阻断核因子-kB的核输入，以抵消炎症信号。我们确认了 两种制剂的体外活性，测量它们在体内的药代动力学，并证实ELP融合防止 他们的胎盘转移，并在先兆子痫的大鼠模型中证明了他们的治疗效果。虽然两者都 药剂在大鼠模型中是有效的，我们相信每一个都可能得到改进。对于ELP融合的血管内皮生长因子，我们 假设一种不同的、血管生成较少的VEGF(VEGF-B167)将具有更强的sFlt-1结合 同时诱导较少的异常血管生成，从而使其成为一种更安全的治疗选择。对于核因子-kB的抑制 多肽，我们已经产生了五个新的多肽，它们针对不同水平的核因子-kB激活级联，并且 我们推测，这些多肽中的一个(或多个组合)将具有更强的抗- 发炎作用。在更新期间，我们将在体外对我们的第二代试剂进行评估，以确认 评价其安全性、药代动力学和治疗效果。 我们的大鼠胎盘缺血模型，为了促进我们的先导药物的翻译，评估他们的 一种新的非人类灵长类妊娠高血压模型--非洲绿猴的安全性和有效性。

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.