Translational Research in Pediatric and Obstetric Pharmacology and Therapeutics

项目概要： 先兆子痫是妊娠的主要并发症，导致显著的围产期死亡率和发病率。它 仍然是一个重大的医学挑战：其原因尚不清楚，也没有有效的治疗方法。因此，目前 护理标准是高度资源密集型的，在很大程度上依赖于包括评估在内的务实措施 已知的危险因素和密切监测血压，尿蛋白，超声波和胎儿。一旦 确诊后，患者接受对症治疗，包括抗高血压药和抗惊厥药， 不涉及疾病机制或进展。通常早产的分娩是唯一的“治愈”方法。虽然 大多数先兆子痫并发症发生在世界上的发展中地区， 在大多数发达国家，孕产妇死亡率下降，美国的孕产妇死亡率实际上 自1990年以来有所增加。一个核心问题是缺乏一种有效的、有针对性的治疗方法来解决疾病 发病机制之前对疾病的缺乏了解和安全问题阻碍了 治疗剂的开发，但最近的发现使其可行。据了解，在 患有先兆子痫的妇女，受压的胎盘会释放“有毒的、循环的”抗血管生成药物， 这些蛋白质进入母亲的血液，清除血管生长因子并破坏血管。临床前和 临床证据表明降低循环中抗血管生成蛋白的浓度是可行的， 从而降低先兆子痫的严重程度。 为了将这一重要知识转化为实际治疗，我们建立了相关的表型 滋养层模型和筛选的360个批准的临床药物，具有良好的安全性在怀孕。 这项试点工作已经确定了有希望的候选药物，显示出治疗潜力， 先兆子痫，减少胎盘释放抗血管生成因子。在目前的工作中，我们将进一步 验证这些药物在相关滋养层和动物中的疗效、药理学和药代动力学 先兆子痫模型，目标是开发转化的药效学-药代动力学数据 与已知的人体剂量接触相衔接。我们还将研究这种新药的潜在机制 方面的影响.在这项研究结束时，我们将选择一个最好的候选人，具有最有利的药理学 和安全性，用于未来在重度先兆子痫患者中的临床试验。 我们创新的再利用策略，通过选择具有良好安全性的临床药物用于妊娠， 避免了传统药物开发过程冗长、成本高昂、风险高的缺点， 将重要的科学转化为临床应用。这项工作的结果将立即支持 在高危患者中进行临床试验如果成功，我们预计将对患者护理产生根本性影响， 健康和社会经济负担。

Project summary: Preeclampsia is a leading complication of pregnancy, causing significant perinatal mortality and morbidity. It remains a major medical challenge: its cause is still unclear, and there is no effective therapy. As a result, current standards of care are highly resource-intensive and largely reliant on pragmatic measures including assessment of known risk factors and close monitoring of blood pressure, urinary protein, ultrasound and the fetus. Once diagnosed, patients receive symptomatic treatment including anti-hypertensives and anti-convulsants, which do not address disease mechanisms or progression. Delivery, often premature, is the only “cure”. Although a majority of preeclampsia complications occur in developing regions of the world, and there has been a steady decline of maternal mortality in most developed nations, maternal mortality in the United States has actually increased since 1990. A central problem is the lack of an effective, targeted therapy that addresses disease pathogenesis. The previous lack of understanding of the disease and safety concerns have hindered development of therapeutic agents, but recent discoveries have made this feasible. It is now understood that in women who are developing preeclampsia, the stressed placenta releases “toxic, circulating” anti-angiogenic proteins into mother's blood, scavenging vascular growth factors and damaging the vasculature. Preclinical and clinical evidence indicates that it is feasible to reduce concentrations of anti-angiogenic proteins in the circulation, and thus to reduce the severity of preeclampsia. To translate this important knowledge into practical treatments, we have established relevant phenotypic trophoblast models and screened 360 approved clinical drugs that have favorable safety profiles in pregnancy. This pilot work has resulted in identification of promising drug candidates that show therapeutic potential for preeclampsia, reducing release of anti-angiogenic factors from the placenta. In the present work, we will further validate the efficacy, pharmacology, and pharmacokinetics of these agents in relevant trophoblast and animal models of preeclampsia, with the goal of developing translational pharmacodynamic-pharmacokinetic data bridging to known human dose exposures. We will also investigate the mechanisms underlying the new drug effects. At the end of this study, we will select one best candidate, that has the most favorable pharmacologic and safety profiles, for a future clinical trial in patients with severe preeclampsia. Our innovative repurposing strategy, by selecting clinical drugs with favorable safety features for pregnancy, circumvents the drawbacks of lengthy, costly, and high-risk conventional drug development, promising to translate important science into clinical use in an efficient way. The outcome of this work will immediately support a clinical trial in high-risk patients. If successful, we expect a fundamental impact on patient care, reducing the health and socioeconomic burdens globally.