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），分为溃疡性结肠炎（UC）和克罗恩病（Crohn's） 疾病（CD），构成了世界范围内流行和增长的临床健康问题。这些 疾病的特征在于使人衰弱的症状，包括腹泻、腹痛和 疲劳和增加患胃肠癌的风险。此外，IBD患者也受到了干扰， 肠道微生物组，称为生态失调。IBD的病因涉及复杂的 免疫遗传变异、环境因素和肠道 微生物组目前IBD的治疗方法包括皮质类固醇和生物制剂，其可以改善炎症反应。 促炎性细胞因子和其他炎症介质的过度产生，但这些介质 不能治疗经常引发或传播炎症的微生物群落失调。此外，长 长期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、消化道疾病、 溃疡、胰腺炎和伤口愈合受损。因此，迫切需要更多的 治疗炎症和微生物群失调的IBD的有效疗法。的特征 IBD亚型UC是炎症结肠组织中高水平嗜中性粒细胞的积累， 对常驻结肠微生物的过度嗜酸性反应。我们的研究团队在 由KeyBiome创始人领导的俄勒冈州大学已经确定了一种新颖的抗炎药物 由斑马鱼肠道共生菌气单胞菌分泌的蛋白质，我们将其命名为免疫气单胞菌 调节剂（AimA）。我们已经证明AimA具有有效的抗炎特性，表明 肠道嗜中性粒细胞减少此外，我们有证据表明AimA有微生物组- 调节活性，包括促炎细菌种类的生长抑制。 因此，AimA提供了开发IBD治疗药物的机会，其独特的能力是 两者都针对炎症的主要介质，中性粒细胞，并促进炎症的恢复。 微生物群落失调在这个项目中，我们将建立AimA治疗的概念数据证明。 在IBD小鼠模型中的功效和微生物群系调节活性。这将激励未来 将AimA开发成一种新型人类治疗药物，为IBD患者提供更多 有效和安全的替代目前的疗法。