Precision therapeutics of inflammatory bowel disease guided by Boolean logic

布尔逻辑指导的炎症性肠病精准治疗

• 批准号: 10249185
• 负责人: Soumita Das
• 金额: $ 31.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-28 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249185
• 关键词: ACVR1 gene; Abscess; Acute; Adjuvant; Adopted; Adult; Age; Agonist; Anti-Inflammatory Agents; Area; Autoimmune Diseases; Biological; Biological Markers; Biological Models; Chemicals; Childhood; Chronic; Chronic Disease; Clinical Research; Clinical Trials; Coculture Techniques; Colitis; Colon; Colorectal Cancer; Companions; Complex; Data Set; Development; Dextrans; Diagnostic; Disease; Disease Progression; Disease remission; Electrical Resistance; Environment; Epithelial; Epithelial Cells; Fistula; Flare; Focus Groups; Gender; Genes; Genetic; Goals; Growth; Human; Immune response; Inflammation; Inflammatory Bowel Diseases; Interview; Knockout Mice; Leadership; Leaky Gut; Logic; Logistics; Maintenance; Maintenance Therapy; Mathematics; Measures; Metabolic; Methods; Microbe; Modeling; Mucositis; Multivariate Analysis; Mus; Organ; Organoids; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Phase; Phase 0 Trial; Phase I/II Trial; Plasma; Precision therapeutics; Process; Recurrent disease; Refractory; Regulator Genes; Relapse; Research; Research Design; Risk; Role; Route; Signal Pathway; Source; Specificity; Stress; Surveys; T cell therapy; Testing; Therapeutic; Tight Junctions; Tissues; Toxic effect; Treatment Efficacy; Validation; Withdrawal; colitis associated cancer; confocal imaging; dextran sulfate sodium induced colitis; disease heterogeneity; disease phenotype; disorder subtype; drug candidate; dysbiosis; efficacy testing; forging; gastrointestinal; healing; host-microbe interactions; human tissue; in vivo; insight; mathematical algorithm; microbial; monolayer; mouse model; nanomolar; novel; occludin; pediatric patients; phase I trial; pre-clinical; prevent; recruit; resilience; response; restoration; screening; small molecule; stressor; synergism; tool; transcriptome sequencing; transcriptomics; trial design

ABSTRACT Disruption of the gut barrier has been implicated in the pathogenesis of multiple chronic illnesses that are characterized by chronic gastrointestinal inflammation. One such illness is inflammatory bowel disease (IBD), a complex, multi-factorial, autoimmune disorder of the gut in which diverse components (microbes, genetics, environment and immune response) intersect in elusive ways and culminate in overt disease 1. It is also heterogeneous with complex sub-disease phenotypes (i.e., strictures, fistula, abscesses, and colitis-associated cancers). Currently, patients are offered inflammation-reducing therapies that have only a ~30-40% response- rate, and 40% of responders become refractory to treatment within one year 2. Little to nothing has emerged that can fundamentally tackle the most widely recognized indicator/predictor of disease relapse, response and remission 3-8, i.e., a compromised epithelial barrier. Among the reasons cited are- 1) incomplete understanding of host-microbe interactions in the gut, and 2) our theoretical inability to pinpoint such a fundamental, actionable and effective target to drive a complex and nebulous process of gut barrier permeability. Preliminary studies using publicly available transcriptomic datasets from adult and pediatric patients with IBD and a set of unbiased novel computational approaches (Boolean implication relationships and Boolean Implication Networks) have pinpointed a novel target, whose activation is predicted to enhance a bona-fide barrier-protective pathway, and thereby, restore the gut barrier across the two subtypes of IBD, despite disease heterogeneity. Expression pharmacology studies using a companion biomarker in FFPE human tissues confirmed that the barrier-protective pathway orchestrated by this target is silenced in patients with IBD. Using a potent and highly specific drug that was previously developed for another indication and found to be safe in Phase I trials on healthy human adults, preliminary evidence has been obtained which shows that activation of the target is necessary and sufficient to trigger the barrier-protective pathway, and for the protection of the epithelial barrier in mice (chemical-induced colitis models) and in murine and human organoid-monolayers challenged with live microbes; it also restored the leaky gut barrier observed in IBD patient-derived organoids. This proposal seeks to validate the repurposing of this potent and specific drug for activating a novel barrier-protective target, the first of its kind, in the treatment of adult and pediatric IBD. Our specific Aims during the 3-y UG3 phase are all geared towards target validation: obtaining proof-of-mechanism in healthy murine and human colon-derived organoids (Aim 1); preclinical proof-of-principle studies using murine models of colitis (Aim 2); and expression pharmacology and proof-of-concept Phase `0' trials in patient-derived organoids (pediatric and adults; Aim 3). Successful demonstration of efficacy in UG3 phase will trigger the UH3-phase (Clinical trial planning; Aim 4). Although the focus here is on barrier-protective therapy to treat/prevent flares in IBD, network analysis revealed that the proposed therapeutic/indication pairing may also inhibit IBD-associated CRCs.

抽象的 肠道障碍的破坏与多种慢性疾病的发病机理有关 以慢性胃肠道炎症为特征。一种疾病是炎症性肠病（IBD），一个 肠道的复杂，多因素，自身免疫性障碍，其中各种成分（微生物，遗传学， 环境和免疫反应）以难以捉摸的方式相交，并在明显的疾病中达到高潮1。 具有复杂的亚疾病表型的异质性（即狭窄，瘘管，脓肿和结肠炎相关 癌症）。目前，为减少炎症的疗法提供了约30-40％的反应 - 比率，有40％的响应者在一年之内对治疗的难治性。几乎没有出现 可以从根本上解决疾病复发，反应和 缓解3-8，即，上皮障碍。在引用的原因之一是-1）不完整的理解 肠道中的宿主 - 微鸟相互作用，以及2）我们的理论无法确定这种基本的可行 并有效地推动肠道屏障渗透性的复杂和模糊的过程。 初步研究使用成人和小儿患者的公开转录组数据集 IBD和一系列公正的新型计算方法（布尔的影响关系和布尔值 暗示网络）已经指出了一个新的目标，该目标被预测会增强善意 尽管疾病 异质性。在FFPE人体组织中使用伴随生物标志物的表达药理学研究 确认IBD患者在该目标中精心策划的屏障保护途径是沉默的。使用 一种有效且高度特异的药物，以前是为另一种迹象而开发的，并在 关于健康人类成年人的第一阶段试验，已经获得了初步证据，这表明激活 目标是必要的，足以触发屏障保护途径，并为保护 小鼠（化学诱导的结肠炎模型）以及鼠和人体器官单层中的上皮屏障 被现场微生物挑战；它还恢复了在IBD患者衍生的类器官中观察到的漏水屏障。 该提案旨在验证这种有效和特定药物的重新利用，以激活一种新颖的药物 障碍保护靶标，是成人和小儿IBD治疗的第一个靶标。我们在 3-Y UG3阶段均针对目标验证：在健康的鼠类和 人类结肠衍生的类器官（AIM 1）；使用鼠类结肠炎模型的临床前原理研究（AIM） 2）;以及表达药理学和概念证明阶段的“ 0”试验（儿科） 和成人；目标3）。在UG3阶段成功证明疗效将触发UH3相（临床试验） 规划;目标4）。尽管这里的重点是屏障保护疗法，以治疗/预防IBD中的耀斑，但 分析表明，提出的治疗/指示配对也可能抑制与IBD相关的CRC。