Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
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DOI：
10.1016/j.ajog.2016.03.001
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发表时间：
2016-07
影响因子：
9.8
通讯作者：
Bidwell G
中科院分区：
文献类型：
--
作者：
Ilekis JV;Tsilou E;Fisher S;Abrahams VM;Soares MJ;Cross JC;Zamudio S;Illsley NP;Myatt L;Colvis C;Costantine MM;Haas DM;Sadovsky Y;Weiner C;Rytting E;Bidwell G
尽管在了解胎盘中涉及妊娠相关疾病病理生理学的分子通路方面取得了很大进展，但在利用这些信息开发新的药物治疗以改善妊娠结局方面仍存在重大差距。2015年3月5日至6日，美国国立卫生研究院尤尼斯·肯尼迪·施莱弗国家儿童健康和人类发展研究所主办了一个为期两天的研讨会，题为《不良妊娠结局的胎盘起源：开始解决这一差距的潜在分子目标》。特别强调了可作为药物靶点的重要分子途径的确定以及以这些特定途径为靶点的利弊。本文是该研讨会会议记录的摘要。涵盖了从基础胎盘生物学到临床试验的广泛主题。这包括对胎盘形成的基础生物学的研究，如滋养层细胞迁移和螺旋动脉重塑，以及滋养层细胞对感染性和非感染性因素的感知和反应。这些领域的研究结果将对制定未来的治疗方法和开发预防一些胎盘性妊娠障碍的治疗方法至关重要，这些疾病包括先兆子痫、胎儿生长受限和子宫炎。研究还总结了美国和欧洲正在进行的临床工作，测试治疗先兆子痫和胎儿生长受限的新干预措施，包括口服精氨酸补充剂、西地那非、普伐他汀、使用病毒传递的血管内皮生长因子的基因疗法和氧气补充疗法。还提出了通过调节胎盘转运蛋白来加强对胎儿的营养转运，以及针对胎盘线粒体功能障碍和氧化应激来改善胎盘健康的战略，以促进胎儿生长。还讨论了microRNAs和胎盘来源的外切体以及信使RNAs用于诊断和作为药物靶标的作用。讲习班讨论了潜在的现有疗法和新疗法的安全性和药代动力学方面的问题，需要特别在妊娠独特的药代动力学特性的背景下加以确定，以及将研究成果转化为实践的障碍和陷阱。研讨会还讨论了在怀孕期间使用纳米颗粒和生物聚合物等大分子载体进行药物输送和靶向的新方法，以最大限度地减少胎盘药物转移和胎儿药物暴露。最后，研讨会形成的一个主要主题是，科学界需要改变他们的想法，即孕妇及其胎儿是脆弱的患者群体，应该避免药物开发，而应将其视为需要更有效治疗干预的贫困人口。
Although much progress is being made in understanding the molecular pathways in the placenta involved in the pathophysiology of pregnancy related disorders, a significant gap exists in utilizing this information for developing new drug therapies to improve pregnancy outcome. On March 5–6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a two day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given in the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of this workshop. A broad number of topics were covered ranging from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and non-infectious agents. Research findings in these areas will be critical for formulating developing future treatments and developing therapies for the prevention of a number of pregnancy disorders of placental origin including preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented summarizing ongoing clinical efforts in the U.S. and in Europe testing novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy using virally-delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by enhancing nutrient transport to the fetus by modulating their placental transporters, as well as targeting placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined especially in the context of the unique pharmacokinetic properties of pregnancy, as well as the hurdles and pitfalls of translating research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy using macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community needs to change their thinking of the pregnant women and her fetus as a vulnerable patient population for which drug development should be avoided, but rather thought of as a deprived population in need of more effective therapeutic interventions.