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

通过使用芯片上的母胎界面开发基于细胞外囊泡的早产疗法

• 批准号: 10434794
• 负责人: Arum Han
• 金额: $ 7.79万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434794
• 关键词: 37 weeks gestation; Address; African American; Animal Model; Anti-Inflammatory Agents; Biological Process; Birth; Birth Rate; Cell membrane; Cell physiology; Cells; Cervix Uteri; Chorion; Clinical Trials; Coculture Techniques; Decidua; Devices; Disease; Disease model; Ensure; Environment; Etiology; Fetal Membranes; Fetus; Future; Gender; Goals; Growth; Health Care Costs; Heterogeneity; Homeostasis; Human; I Kappa B-Alpha; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Lead; Lipopolysaccharides; Maternal-Fetal Exchange; Mediator of activation protein; Membrane; Modeling; Mus; NF-kappa B; Nutrient; Organ; Oxidative Stress; Pathologic; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physiological; Pilot Projects; Placenta; Pregnancy; Pregnancy Complications; Pregnancy Maintenance; Premature Birth; Premature Labor; Prevention strategy; Process; Property; Race; Reporting; Research; Risk; Risk Factors; Sampling; Side; Structure; System; Teratogens; Testing; Therapeutic; Tissue Microarray; Tissues; Toxic effect; Transgenic Mice; Tumor-infiltrating immune cells; United States; Uterine Contraction; Uterus; amnion; base; cost; drug mechanism; efficacy testing; engineered exosomes; extracellular vesicles; fetal; healthy pregnancy; in utero; in vivo; inhibitor/antagonist; innovative technologies; male; microbial; migration; model design; mouse model; neglect; neonatal death; neonatal morbidity; neonate; nonhuman primate; novel; novel therapeutics; organ on a chip; personalized care; preclinical trial; premature; racial diversity; response; side effect; stem cells; success; therapeutic candidate; therapeutic development; therapy design; trafficking; trophoblast

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.

抽象的 自发性早产 (PTB) 约占所有早产的 60%（每年 1500 万个 PTB，100 万个 全球新生儿死亡）。胎儿和母体的免疫稳态保持平衡。 妊娠维持和胎儿胎盘生长的免疫稳态的过早破坏。 由于传染性或其他非传染性危险因素导致的压倒性宿主炎症反应导致大多数 过去几十年来，PTB 的发生率并未下降，而且当前的 PTB 预防策略也没有下降。 解决胎儿免疫反应，这是引发早产的关键介质。 使用一种创新技术来设计外泌体，使其富含 NF-κB 抑制剂，称为超级抑制剂 使用转基因小鼠模型进行的初步研究表明，阻遏蛋白 IκBα [SR] 成功延迟了 PTB，且没有任何影响。 与母胎界面组织炎症减少相关的副作用（F-M； 膜细胞和母体蜕膜）然而，将其转移到下一阶段具有挑战性，因为它非常大。 非人类灵长类动物的数量，最接近人类 F-M 界面的动物模型，将是 需要一个忠实代表结构的片上器官（OOC）模型， 人类 F-M 界面的功能和响应可以克服这些挑战。 最近报道了第一个F-M界面OOC模型，该模型被成功地用于展示交互和 原代细胞的过渡特性，在子宫内重新组装其生物学功能，该模型。 将扩展包括完整的F-M界面，重建健康和疾病炎症状态，并充分 对其细胞功能和易患 PTB 的反应进行验证 UG3 的目标是： 目标 1 验证。 F-M 界面 OOC 模型； 目标 2 建立疾病 F-M 界面 OOC 模型 UH3 的目标是： 目标 3 在正常和正常小鼠身上测试细胞外囊泡 (EV) 编码的实验药物 NF-kB 阻遏物 (SR) 疾病F-M界面OOC模型；目标4 使用OOC模型进行临床前试验以进行研究 种族多样性和胎儿性别对实验药物疗效的影响。 拟议研究的一部分将产生一个个性化的 F-M 界面 OOC 模型，可以模仿健康或 妊娠疾病状态，可用于测试候选治疗分子加速的效果 临床试验的流程和/或消除/最小化昂贵的临床试验中的某些步骤。