Developing extracellular vesicle based therapeutics against pre-term birth through the use of maternal-fetal interface on a chip

摘要 自然早产占所有早产的60%(每年1500万早产和100万早产 全球新生儿死亡人数)。胎儿和母体间的平衡免疫动态平衡确保 妊娠维持和胎盘发育。过早破坏免疫动态平衡和 由感染性或其他非感染性危险因素引起的压倒性宿主炎症反应导致大多数 PTB的数量。肺结核发病率在过去几十年里没有下降，目前的结核病预防策略也没有下降 解决胎儿免疫反应，这是触发早产的关键媒介。求婚团队最近 使用一项创新技术设计了富含核因子-κB抑制剂的外切体，称为超级 抑制物IκBα[SR]。使用转基因小鼠模型的初步研究显示，在没有任何 与母胎界面组织炎症减轻相关的副作用(F-M；胎儿 膜细胞和母体蜕膜)。然而，将这一点转移到下一阶段是具有挑战性的，因为 非人类灵长类的数量，最接近人类F-M界面的动物模型，将是 这是需要的，这是成本高昂的。忠实地代表结构的芯片上器官(OOC)模型， 人的F-M接口的功能和响应可以克服这些挑战。提出申请的团队已经 最近报道了第一个F-M接口OOC模型，该模型成功地用于显示交互和 原始细胞的过渡性，类似于它们在子宫中的生物学功能。在UG3阶段，该模型 将扩展到包括完整的F-M界面，重新创建健康和疾病炎症状态，并完全 确认他们的细胞功能和易患肺结核的反应。UG3的目标是：目标1验证 F-M界面OOC模型；目的2建立疾病F-M界面OOC模型。UH3的目标是： 目的3检测细胞外囊泡(EV)编码的实验药物核因子-kB抑制物(SR)在正常和 疾病F-M界面OOC模型；目的4使用OOC模型进行临床前试验 种族多样性和胎儿性别对实验药物疗效的影响。成功之路 将产生一个个性化的F-M接口OOC模型，它可以模仿健康或 妊娠疾病状态，可以用来测试候选治疗分子的效果，以加快 临床试验过程和或取消/最大限度地减少昂贵的临床试验的某些步骤。

ABSTRACT Spontaneous preterm birth (PTB) accounts for ~60% of all preterm births (15 million PTBs/year and 1 million neonatal deaths around the globe). Balanced immune homeostasis by fetal and maternal compartments ensure pregnancy maintenance and feto-placental growth. Premature disruption of immune homeostasis and overwhelming host inflammatory response due to infectious or other non-infectious risk factors lead to majority of PTBs. PTB rate has not declined in the past several decades, and current PTB prevention strategies do not address fetal immune responses, a key mediator that triggers preterm labor. The proposing team has recently used an innovative technology to engineer exosomes to be enriched with an inhibitor to NF-κB, termed as super repressor IκBα [SR]. Pilot studies using a transgenic mouse model showed successful delay in PTB without any side effects that was associated with reduction in inflammation at the feto-maternal interface tissues (F-M; fetal membrane cells and maternal decidua). However, moving this to the next stage is challenging, as a very large number of non-human primates, the animal model that most closely resemble the human F-M interface, will be needed, which is cost prohibitive. An organ-on-chip (OOC) model that faithfully represents the structure, functions, and responses of human F-M interface can overcome such challenges. The proposing team has recently reported the first F-M interface OOC model, which was successfully utilized to show the interactive and transitional properties of primary cells, resembling their biological functions in utero. In the UG3 phase, this model will be expanded to include the full F-M interface, recreate a healthy and disease inflammatory state, and fully validated for their cellular functions and responses predisposing to PTB. The UG3 aims are: Aim 1 To validate the F-M interface OOC model; Aim 2 To establish disease F-M interface OOC models. The UH3 aims are: Aim 3 To test extracellular vesicle (EV)-encoded experimental drug NF-kB repressor (SR) on normal and disease F-M interface OOC models; Aim 4 Conduct pre-clinical trial using the OOC model to investigate the impact of racial diversity and gender of fetus on the efficacy of the experimental drug. The success of the proposed research will produce a personalized F-M interface OOC model that can mimic either healthy or disease state of pregnancy, which can be used to test the effect of candidate therapeutic molecules to expedite processes towards clinical trials and or eliminate/minimize certain steps from expensive clinical trials.