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: 10037855
• 负责人: Arum Han
• 金额: $ 69.1万
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10037855
• 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; 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 自发早产（PTB）占所有早产的约60％（1500万PTB和100万 全球新生儿死亡）。通过胎儿和孕产妇室的平衡免疫稳态确保 妊娠维持和胎儿置换生长。免疫稳态过早中断和 由于传染性或其他非感染风险因素而导致的压倒性宿主炎症反应导致多数 PTBS。在过去的几十年中，PTB率没有下降，当前的PTB预防策略没有 解决胎儿免疫反应，这是一种触发早产劳动的关键介体。提案团队最近有 使用创新技术来设计外泌体，以富含抑制剂到NF-κB，称为超级 阻遏物IκBα[SR]。使用转基因小鼠模型的试验研究显示，PTB成功延迟了没有任何 副作用与胎儿界面组织的炎症减少有关（F-M;胎儿 膜细胞和母体Decidua）。但是，将其移至下一阶段是挑战的，因为很大 非人类素数的数量，最类似于人类F-M接口的动物模型将是 需要，这是禁止成本的。忠实地代表结构的芯片（OOC）模型 人类F-M界面的功能和响应可以克服此类挑战。提案团队有 最近报道了第一个F-M接口OOC模型，该模型已成功地显示了交互式和 原代细胞的过渡性能，类似于其在子宫内的生物学功能。在UG3阶段，此模型 将扩展到包括完整的F-M接口，重新创建健康和疾病的炎症状态，并完全 验证了其细胞功能和响应偏见于PTB。 UG3的目的是：目标1验证 F-M接口OOC模型；目标2建立疾病F-M接口OOC模型。 UH3的目的是： AIM 3以正常和 疾病F-M接口OOC模型； AIM 4使用OOC模型进行临床前试验进行研究 种族多样性和胎儿性别对实验药物效率的影响。成功 在拟议的研究中，将产生个性化的F-M接口OOC模型，该模型可以模仿健康或 疾病的怀孕状态，可用于测试候选疗法分子的影响以加快 临床试验的过程，或消除/最小化昂贵临床试验中的某些步骤。