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.

摘要 肠道屏障的破坏被认为与多种慢性疾病的发病机制有关 以慢性胃肠道炎症为特征。其中一种疾病是炎症性肠病(IBD)，一种 一种复杂的、多因素的、自身免疫性肠道疾病，其中不同的成分(微生物、遗传学、 环境和免疫反应)以难以捉摸的方式相交，最终导致显性疾病1。它也是 具有复杂亚疾病表型(即狭窄、瘘管、脓肿和结肠炎相关)的异质性 癌症)。目前，为患者提供的消炎治疗只有30%-40%的反应- 发生率，40%的应答者在一年内对治疗产生抵抗力2。 可以从根本上解决最广泛认可的疾病复发、反应和预测指标/预测因素 缓解3-8，即受损的上皮屏障。其中提到的原因包括：1)理解不完整 肠道中宿主-微生物的相互作用，以及2)我们在理论上无法准确定位这样一个基本的、可操作的 和有效的靶点，推动肠道屏障通透性的复杂而模糊的过程。 使用来自成人和儿童患者的公开可用转录数据集进行的初步研究 IBD和一组新的无偏计算方法(布尔蕴涵关系和布尔 隐含网络)已经确定了一个新的目标，该目标的激活被预测将增强真正的 屏障保护途径，从而恢复跨越两种亚型IBD的肠道屏障，尽管有疾病 异质性。利用伴随生物标记物在FFPE人体组织中的表达药理学研究 证实在IBD患者中，由该靶点协调的屏障保护途径是沉默的。vbl.使用 一种强效且高度特异的药物，以前为另一种适应症而开发，并被发现在 在健康成人身上进行的I期试验，已经获得了初步证据，表明激活 靶标是触发屏障保护途径的必要条件和充分条件，并且对于保护 小鼠(化学性结肠炎模型)、小鼠和人器官单层的上皮屏障 用活的微生物挑战；它还恢复了IBD患者衍生的有机物质中观察到的渗漏的肠道屏障。 这项提案试图验证这种有效和特定的药物的再用途，以激活一种新的 第一个屏障保护靶点，用于成人和儿童IBD的治疗。我们的具体目标是 3-y UG3阶段都面向靶标验证：在健康小鼠和 人类结肠衍生有机化合物(AIM 1)；使用小鼠结肠炎模型进行的临床前原则验证研究(AIM) 2)；患者衍生有机化合物的表达、药理学和概念验证阶段试验(儿科 和成年人；目标3)。UG3阶段疗效的成功演示将触发UH3阶段(临床试验 规划；目标4)。虽然这里的重点是屏障保护性疗法来治疗/预防IBD的红斑， 分析表明，拟议的治疗/适应症配对也可能抑制IBD相关的CRC。