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: 10047127
• 负责人: Soumita Das
• 金额: $ 31.51万
• 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/10047127
• 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; Epithelium; 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 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。一种这样的疾病是炎症性肠病（IBD）， 肠道的复杂的、多因素的自身免疫性疾病，其中多种成分（微生物，遗传学， 环境和免疫反应）以难以捉摸的方式相交，并最终导致明显的疾病1。也是 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，为患者提供的抗炎治疗只有约30-40%的反应， 率，40%的应答者在一年内变得难以治疗2。几乎没有任何证据表明， 可以从根本上解决最广泛认可的疾病复发、反应和 缓解3-8，即，受损的上皮屏障其中列举的原因有：1）不完全理解 肠道中宿主-微生物相互作用的影响，以及2）我们理论上无法确定这种基本的，可操作的 和有效的目标，以推动一个复杂的和模糊的过程，肠道屏障的渗透性。 使用来自成人和儿童患者的公开可用转录组数据集的初步研究， IBD和一组无偏的新的计算方法（布尔蕴涵关系和布尔 暗示网络）已经确定了一个新的目标，其激活预计将增强一个真正的 屏障保护途径，从而恢复肠道屏障跨越两种亚型的IBD，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 证实了在IBD患者中，由该靶点协调的屏障保护途径是沉默的。使用 这是一种强效且高度特异性的药物，以前曾开发用于另一种适应症， 在健康成年人的I期试验中，已经获得了初步证据，其显示， 该目标是必要的，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）以及鼠和人类器官单层中的上皮屏障 用活微生物挑战;它还恢复了IBD患者来源的类器官中观察到的肠道屏障渗漏。 该提案旨在验证这种强效和特异性药物的再利用，以激活新的 屏障保护靶点，这是同类产品中的第一个，用于治疗成人和儿童IBD。我们的具体目标 3-yUG 3阶段都是为了靶向验证：在健康鼠中获得机制证明， 人结肠源性类器官（Aim 1）;使用结肠炎小鼠模型的临床前原理验证研究（Aim 2）;以及在患者源性类器官（儿科）中进行的表达药理学和概念验证“0”期试验 成人;目标3）。在UG 3期成功证明疗效将触发UH 3期（临床试验 规划;目标4）。虽然这里的重点是屏障保护治疗，以治疗/预防炎症性肠病，网络 分析显示，所提出的治疗/适应症配对也可能抑制IBD相关的CRC。