Novel Therapeutic Approaches For Treatment of Intestinal Inflammation

治疗肠道炎症的新方法

基本信息

批准号：
9232271
负责人：
Timothy L Denning
金额：
$ 34.09万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9232271
关键词：
Acute Adverse effects Affect Alginates Anti-Tumor Necrosis Factor Therapy Antigen-Presenting Cells Biological Process Cell Differentiation process Cells Chitosan Chronic Clinic Colitis Colon Crohn&apos s disease Data Development Disease Dose Encapsulated Epithelial Etiology FOXP3 gene Homing Human Hydrogels In Vitro Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Interleukin-12 Intestines Malignant Neoplasms Mediating Modeling Monoclonal Antibodies Opportunistic Infections Oral Oral Administration Pathogenesis Patients Pharmaceutical Preparations Play Production Recombinants Regimen Regulatory T-Lymphocyte Role Severity of illness Site Small Interfering RNA Symbiosis TNF gene Testing Toxic effect Ulcerative Colitis United States Wound Healing adaptive immune response cytokine dosage improved in vivo infliximab innovation interleukin-22 interleukin-23 macrophage microbiota mouse model nanoparticle novel novel strategies novel therapeutic intervention repaired targeted treatment

项目摘要

Summary The two most common forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, affect approximately 1.4 million people in the United States. The etiology of IBD is unclear, yet aberrant innate and adaptive immune responses directed towards the commensal microbiota are believed to underlie disease pathogenesis. Numerous pro-inflammatory factors contribute to disease severity and targeting some of these factors has proven effective in the treatment of IBD patients. TNFα in particular plays a crucial role as a pro- inflammatory mediator in the pathogenesis of IBD and the anti-TNFα monoclonal antibody, infliximab, is now successfully used in the clinic to treat human IBD. However, anti-TNFα therapy is only effective in a subset of IBD patients and concerns remain regarding adverse effects, such as cancer and opportunistic infections. The observed adverse effects are mainly due to the lack of targeted treatment and the “over dosage” that is usually inherent to systemic drug administration. More recently, a monoclonal antibody targeting IL-12 and IL-23, ustekinumab, was shown to be effective in IBD patients, especially those in which anti-TNFα therapy had previously failed. Thus, treatment of human IBD may be optimized by novel delivery regimens that allow for targeted, low-dose inhibition of both TNF-α and IL-12/23. We have demonstrated that oral administration of nanoparticles loaded with TNFα siRNA and encapsulated in an alginate-chitosan hydrogel can be efficiently targeted to the colon without toxicity and reduce intestinal inflammation in a mouse model. Our exciting preliminary data demonstrate that specific targeting of nanoparticles containing siRNA to intestinal antigen presenting cells may enhance the beneficial effects of this novel therapeutic approach. In the course of these studies, we also discovered that inhibition of pro-inflammatory cytokines can have the unexpected side effect of inhibiting critical wound-healing factors, such as IL-22. These finding have led us to propose that nanoparticle-mediated manipulation of TNFα, IL-12/23 and IL-22 limits intestinal inflammation and promotes wound healing during IBD. These novel strategies aimed at locally inhibiting key pro-inflammatory cytokines while simultaneously promoting wound healing may contribute to the development of improved therapies for the treatment of human IBD.

概括炎症性肠病（IBD）的两种最常见形式，克罗恩病和溃疡性结肠炎，在美国影响约140万人。 IBD的病因尚不清楚，但异常的天生据信针对共生微生物群的自适应免疫调查是疾病的基础发病。许多促炎性因素导致疾病的严重程度，并针对其中一些事实证明，因素有效地治疗IBD患者。尤其是TNFα作为促进作用至关重要 IBD发病机理和抗TNFα单克隆抗体英夫利昔单抗中的炎症介质现在为在诊所成功使用以治疗人类IBD。但是，抗TNFα治疗仅在一部分中有效 IBD患者和对不良反应（例如癌症和机会性感染）的担忧仍然存在。这观察到的不良反应主要是由于缺乏靶向治疗和通常是“过度剂量” 系统药物管理固有。最近，靶向IL-12和IL-23的单克隆抗体， ustekinumab被证明对IBD患者有效，尤其是那些抗TNFα治疗的患者以前失败了。这是通过新型分娩方案来优化人类IBD的处理，允许针对TNF-α和IL-12/23的靶向低剂量抑制。我们已经证明了口头管理装有TNFαsiRNA并封装在算法 - 壳聚糖水凝胶中的纳米颗粒可以有效针对无毒性的结肠并减少小鼠模型中的肠炎。我们令人兴奋初步数据表明，含有siRNA到肠道抗原的纳米颗粒的特定靶向呈现细胞可能会增强这种新型热方法的有益效果。在这些过程中研究，我们还发现抑制促炎性细胞因子可能具有意外的副作用抑制关键伤口治疗因子，例如IL-22。这些发现使我们提出纳米颗粒介导的TNFα，IL-12/23和IL-22的操纵肠道注射限制并促进 IBD期间的伤口愈合。这些新型策略旨在局部抑制关键的促炎细胞因子同时促进伤口愈合可能有助于发展改进的疗法人类IBD的处理。