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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.

摘要