Aim protein-based anti-inflammatory therapeutic for the treatment of IBD

基于蛋白质的抗炎疗法治疗 IBD

• 批准号: 10822016
• 负责人: Catherine Pohl Robinson
• 金额: $ 22.84万
• 依托单位: KEYBIOME LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10822016
• 关键词: Abdominal Pain; Adherent Invasive Escherichia coli; Adrenal Cortex Hormones; Adverse effects; Aeromonas; Anti-Inflammatory Agents; Antibodies; Bacteria; Biological Assay; Biological Models; Biological Products; Chemicals; Chronic; Clinical; Colitis; Colonic inflammation; Complex; Crohn' s disease; Data; Detection; Development; Diagnostic; Diarrhea; Diet; Disease; Disease remission; Drug Kinetics; Enteral; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Etiology; Fatigue; Formulation; Future; Gnotobiotic; Goals; Growth; Health; Human; Immunologics; Immunomodulators; Impaired wound healing; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Investigation; Legal patent; Long-Term Effects; Malignant neoplasm of gastrointestinal tract; Measures; Modeling; Mus; Names; Oregon; Osteoporosis; Pancreatitis; Pathology; Patients; Peptic Ulcer; Phase; Phenotype; Process; Production; Property; Protein Secretion; Proteins; Research; Risk; Safety; Sampling; Serum; Small Business Technology Transfer Research; Source; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; Ulcerative Colitis; Universities; Variant; Work; Zebrafish; clinically relevant; colon microbiota; cytokine; disabling symptom; disorder subtype; dysbiosis; effective therapy; genetic variant; gut inflammation; gut microbiome; immunoregulation; inflammatory marker; microbial; microbial community; microbiome; mouse model; murine colitis; neutrophil; novel; novel therapeutics; pathobiont; preclinical efficacy; preclinical safety; prophylactic; protein phosphatase inhibitor-2; response; restoration; screening; side effect; symbiont; therapeutic evaluation

Inflammatory bowel disease (IBD), which is subdivided into ulcerative colitis (UC) and Crohn’s disease (CD), constitutes a prevalent and growing clinical health problem worldwide. These diseases are characterized by debilitating symptoms including diarrhea, abdominal pain, and fatigue, and increased risk of gastrointestinal cancers. In addition, IBD patients have perturbed intestinal microbiomes, referred to as dysbiosis. The etiology of IBD involves complicated interactions between immunological genetic variants, environmental factors, and the intestinal microbiome. Current therapies for IBD include corticosteroids and biologics, which can ameliorate overproduction of pro-inflammatory cytokines, and other inflammatory mediators, but which do not treat the microbiome dysbiosis that often triggers or propagates inflammation. In addition, long term use of corticosteroids and biologics has serious side effects, including osteoporosis, peptic ulcers, pancreatitis, and impaired wound healing. Therefore, an urgent need exists for more effective therapies for IBD that treat both inflammation and microbiome dysbiosis. A feature of the IBD subtype UC is the accumulation of high levels of neutrophils in inflamed colonic tissues and an excessive neutrophilic response to resident colonic microbes. Our research team at the University of Oregon, led by the founders of KeyBiome, has identified a novel anti-inflammatory protein secreted by a zebrafish gut symbiont, Aeromonas, which we named Aeromonas immune modulator (AimA). We have shown that AimA has potent anti-inflammatory properties, indicated by a reduction in intestinal neutrophils. Moreover, we have evidence that AimA has microbiome- modulating activities that include growth inhibition of pro-inflammatory bacterial species. Therefore, AimA presents an opportunity to develop a therapeutic for IBD, unique in its ability to both target a primary mediator of inflammation, neutrophils, and facilitate restoration of microbiome dysbiosis. In this project we will establish proof of concept data for AimA’s therapeutic efficacy and microbiome-modulating activity in a mouse model of IBD. This will motivate future development of AimA into a novel human therapeutic to offer patients suffering from IBD a more effective and safer alternative to current therapies.

炎症性肠病（IBD）被细分为溃疡性结肠炎（UC）和克罗恩 疾病（CD）构成了全球普遍存在的临床健康问题。这些 疾病的特征是使包括腹泻，腹痛和 疲劳，并增加胃肠道癌的风险。此外，IBD患者遭受了干扰 肠道微生物组，称为营养不良。 IBD的病因涉及复杂 免疫遗传变异，环境因素和肠道之间的相互作用 微生物组。 IBD的当前疗法包括皮质类固醇和生物制剂，可以改善 促炎性细胞因子和其他炎症介质的过量生产，但确实如此 不治疗经常触发或传播注射的微生物组营养不良。另外，很长 术语使用皮质类固醇和生物制剂具有严重的副作用，包括骨质疏松症，胡椒粉 溃疡，胰腺炎和伤口愈合受损。因此，迫切需要更多 同时治疗注射和微生物组营养不良的IBD的有效疗法。一个功能 IBD亚型UC是在发炎的结肠组织和 对居民结肠微生物的嗜中性粒细胞反应过多。我们的研究团队 由KeyBiome的创始人领导的俄勒冈大学已经确定了一种新颖的抗炎药 斑马鱼肠道符号Aeromonas分泌的蛋白质，我们将其命名为Aeromonas Immune 调节器（AIMA）。我们已经表明，AIMA具有潜在的抗炎特性，表明 通过减少肠中性粒细胞。此外，我们有证据表明AIMA具有微生物组 - 调节活性，包括促炎细菌的生长抑制。 因此，AIMA提供了一个为IBD开发理论的机会，它具有独特的能力 两者都针对炎症，中性粒细胞的主要介体以及促进的恢复 微生物组营养不良。在这个项目中，我们将为AIMA疗法建立概念数据证明 IBD小鼠模型中的功效和微生物组调节活性。这将激发未来 将AIMA开发为一种新型的人类疗法，以更多地为患有IBD的患者提供更多 当前疗法有效，更安全的替代品。