Targeted Inhibition of Interleukin-1 beta to Prevent Preterm Birth

靶向抑制白细胞介素 1 β (IL-1 beta) 预防早产

基本信息

批准号：
10617680
负责人：
KRISTINA M. ADAMS WALDORF
金额：
$ 76.82万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-11 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617680
关键词：
Acids Amino Acids Amniotic Fluid Anatomy Animal Model Animals Antibiotics Apical Area Under Curve Bacteria Bacterial Infections Birth Brain Caring Catheterization Cells Cesarean section Chorion Chorionic villi Chronic Clinical Colon Continuous Infusion Cytokine Network Pathway Data Decidua Development Dimensions Dose Drug Kinetics Escherichia coli FDA approved Fetal Lung Fetal safety Fetus Flow Cytometry Funding Gene Expression Half-Life Histopathology Hormonal Human Immune response Immunologics Induced Labor Indwelling Catheter Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Infiltrate Injury Interleukin-1 Interleukin-1 Receptors Interleukin-1 beta Intervention Intravenous Bolus Invaded Kineret Letters Lipopolysaccharides Lung Mass Spectrum Analysis Maternal-Fetal Exchange Mediating Membrane Methods Modeling Molecular Target Mus Names Neonatal Mortality Outcome Pathway interactions Peptides Perinatal Perinatal mortality demographics Pharmaceutical Preparations Placenta Placentation Plasma Population Pregnancy Pregnant Women Premature Birth Premature Labor Prevention Prostaglandins Publishing Rattus Research Safety Sampling Signal Transduction Specificity Sterility Streptococcal Infections Streptococcus Group B Testing Therapeutic Time Tissues Translations Treatment Efficacy Uterine Contraction Uterine Monitoring Uterus Vagina Zika Virus adverse pregnancy outcome amnion amniotic cavity anakinra antagonist antenatal clinically significant cytokine digital effective therapy efficacy evaluation efficacy testing experimental study fetal fetal blood gene regulatory network infant death inhibitor intraamniotic infection manufacture microbial neonatal death neonatal morbidity neonatal sepsis neonate new technology nonhuman primate novel pathogen preclinical study pregnant prevent primary outcome protein expression reproductive reproductive toxicity secondary outcome single-cell RNA sequencing stillbirth therapeutic evaluation transcriptomic profiling

项目摘要

PROJECT SUMMARY/ABSTRACT Preterm birth remains a significant cause of neonatal morbidity and mortality. Intra-amniotic infection and inflammation are important triggers for early preterm birth, which is associated with fetal injury mediated by cytokines and other inflammatory mediators in the amniotic fluid and fetus. The objective of this proposal is to establish the efficacy and safety of a novel selective allosteric interleukin-1 receptor (IL-1R) inhibitor (Rytvela) as an antenatal therapeutic strategy to prevent fetal injury and PTB. In pregnant mice, we have strong evidence that Rytvela is a potent suppressor of preterm birth and fetal injury induced by either lipopolysaccharide or lipotechoic acid. To enable translation of these discoveries to human pregnancy, we propose to test the efficacy and determine pharmacokinetics of Rytvela in a pregnant nonhuman primate model of preterm labor induced by Group B Streptococcus (GBS), a clinically important bacterium that colonizes the vagina and can cause preterm labor and neonatal sepsis. Our unique chronically catheterized nonhuman primate model has the greatest relevance to human pregnancy of any animal model and allows sampling in normally inaccessible compartments (amniotic fluid, maternal and fetal blood) multiple times without disrupting the pregnancy. New preliminary studies added to this resubmission demonstrate: 1) inhibition of preterm birth by Rytvela for at least 7 days (clinically significant endpoint), 2) determination of Rytvela pharmacokinetics in a rat model, 3) ability to quantify Rytvela using mass spectrometry in plasma for pharmacokinetics studies, and 3) incorporation of novel technology (Digital Spatial Profiling) to study immune responses at the maternal-fetal interface. In Aim 1, we will determine Rytvela pharmacokinetics in our NHP model and establish if IL-1 inhibition by Rytvela delays the onset of GBS-induced preterm labor. Aim 2 will determine if IL-1 inhibition by Rytvela can ameliorate inflammatory injury to the placenta, fetal lung and brain using three high-throughput multiplexed analyses: 1) multidimensional flow cytometry to quantitate cell populations, 2) Digital Spatial Profiling to interrogate immunologic protein expression and pathway activation in discrete tissues (amnion, chorion, decidua) of the placental chorioamniotic membranes, and 3) single cell RNA-Seq for transcriptomic profiling of regulatory gene networks within single cells in placental tissues. These experiments represent a natural progression of preliminary studies in multiple animal models and are essential to determining whether IL-1 is a viable molecular target for the prevention of preterm birth and fetal protection.

项目概要/摘要早产仍然是新生儿发病和死亡的一个重要原因。羊膜内感染和炎症是早期早产的重要触发因素，这与以下因素介导的胎儿损伤有关：羊水和胎儿中的细胞因子和其他炎症介质。该提案的目标是确定新型选择性变构白细胞介素 1 受体 (IL-1R) 抑制剂的有效性和安全性（Rytvela）作为预防胎儿损伤和 PTB 的产前治疗策略。在怀孕的小鼠中，我们有强有力的证据表明 Rytvela 是早产和胎儿损伤的有效抑制剂脂多糖或脂磷壁酸。为了将这些发现转化为人类怀孕，我们提议在怀孕的非人灵长类动物模型中测试 Rytvela 的功效并确定其药代动力学 B 族链球菌 (GBS) 引起的早产，GBS 是一种临床上重要的细菌，定植于阴道，可导致早产和新生儿败血症。我们独特的长期插管的非人类灵长类动物在所有动物模型中，该模型与人类怀孕的相关性最大，并且允许在正常情况下进行采样多次对难以进入的隔室（羊水、母血和胎儿血液）进行多次处理，而不会破坏怀孕。本次重新提交中添加的新初步研究表明：1）通过以下方式抑制早产： Rytvela 至少 7 天（临床显着终点），2) 测定 Rytvela 在大鼠中的药代动力学模型，3) 使用血浆质谱法量化 Rytvela 进行药代动力学研究的能力，以及 3) 结合新技术（数字空间分析）来研究母胎的免疫反应界面。在目标 1 中，我们将确定 Rytvela 在 NHP 模型中的药代动力学，并确定 IL-1 抑制是否有效 Rytvela 可以延迟 GBS 引起的早产的发生。目标 2 将确定 Rytvela 抑制 IL-1 是否可以使用三种高通量多重方法改善胎盘、胎儿肺和大脑的炎症损伤分析：1) 多维流式细胞术定量细胞群，2) 数字空间分析研究离散组织（羊膜、绒毛膜、蜕膜）中的免疫蛋白表达和通路激活胎盘绒毛膜羊膜的分析，以及 3) 单细胞 RNA-Seq 用于调节转录组学分析胎盘组织单细胞内的基因网络。这些实验代表了一个自然的进展在多种动物模型中进行的初步研究对于确定 IL-1 是否是一种可行的分子至关重要预防早产和保护胎儿的目标。