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

基本信息

批准号：
10709716
负责人：
Pradipta Ghosh
金额：
$ 35.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2020-08-28 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10709716
关键词：
ACVR1 gene Abscess Acute Adjuvant Adopted Adult Age Agonist Anti-Inflammatory Agents Area Autoimmune Diseases Biological Markers Biological Models Biological Products Childhood Chronic Chronic Disease Clinical Research Clinical Trials Colon Colorectal Cancer Companions Complex Data Set Development Dextrans Diagnostic Disease Disease Progression Disease remission Electrical Resistance Environment 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 National Center for Advancing Translational Sciences 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 Rationalization Recurrent disease Refractory Research Research Design Risk Reduction Role Route Signal Pathway Source Specificity Stress Surveys T cell therapy Testing Therapeutic Tight Junctions Tissues Toxic effect Treatment Efficacy Validation Withdrawal chemically induced colitis colitis associated cancer confocal imaging dextran sulfate sodium induced colitis disease heterogeneity disease phenotype disorder subtype drug candidate dysbiosis efficacy testing forging gastrointestinal gene regulatory network healing host-microbe interactions human tissue in vivo insight mathematical algorithm microbial microbial products monolayer murine colitis nanomolar novel occludin patient retention pediatric patients phase I trial pre-clinical prevent protective pathway recruit resilience response restoration screening small molecule stressor synergism tool transcriptome sequencing transcriptomics trial design trial planning

项目摘要

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.

抽象的肠道屏障的破坏与多种慢性疾病的发病机制有关，这些疾病以慢性胃肠道炎症为特征。其中一种疾病是炎症性肠病（IBD），一种复杂的、多因素的、自身免疫性肠道疾病，其中多种成分（微生物、遗传学、环境和免疫反应）以难以捉摸的方式交叉并最终导致明显的疾病 1。具有复杂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，向患者提供的消炎疗法仅产生约 30-40% 的反应 - 率，并且 40% 的应答者在一年内变得难以治疗 2。几乎没有发现任何迹象表明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/预测缓解3-8，即上皮屏障受损。引用的原因包括 - 1）不完全理解肠道中宿主-微生物相互作用的研究，以及2）我们理论上无法确定这样一个基本的、可操作的驱动肠道屏障通透性复杂而模糊的过程的有效目标。使用来自成人和儿科患者的公开转录组数据集进行的初步研究 IBD 和一组无偏新颖的计算方法（布尔蕴涵关系和布尔 Implication Networks）已经确定了一个新的目标，预计其激活将增强真实性屏障保护途径，从而恢复 IBD 两种亚型的肠道屏障，尽管疾病异质性。使用 FFPE 人体组织中的伴随生物标志物进行表达药理学研究证实由该靶标精心策划的屏障保护途径在 IBD 患者中被沉默。使用一种强效且高度特异性的药物，之前针对另一种适应症而开发，并被发现在以下情况下是安全的：对健康成人进行的 I 期试验，已获得初步证据表明，激活该目标对于触发屏障保护途径以及保护小鼠（化学诱导的结肠炎模型）以及小鼠和人类类器官单层中的上皮屏障受到活微生物的挑战；它还恢复了在 IBD 患者来源的类器官中观察到的漏肠屏障。该提案旨在验证这种有效且特定的药物的重新利用，以激活一种新型药物屏障保护靶点，首个用于治疗成人和儿童 IBD 的靶点。我们的具体目标 3 年 UG3 阶段均面向目标验证：在健康小鼠和人类结肠来源的类器官（目标 1）；使用小鼠结肠炎模型进行临床前原理验证研究（Aim 2）；和表达药理学和概念验证“0”期试验的患者来源的类器官（儿科和成人；目标3）。 UG3期功效的成功证明将触发UH3期（临床试验规划;目标 4)。尽管这里的重点是治疗/预防 IBD 发作的屏障保护疗法，但网络分析表明，所提出的治疗/适应症配对也可能抑制 IBD 相关的 CRC。