Selective induction of endogenous IL10 for the treatment of uveitis

选择性诱导内源性 IL10 治疗葡萄膜炎

• 批准号: 8648778
• 负责人: Jack Tzu-Chiao Lin
• 金额: $ 22.17万
• 依托单位: ANVIL BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648778
• 关键词: Acute; Adrenal Cortex Hormones; Adverse effects; Anterior uveitis; Anti-Inflammatory Agents; Anti-inflammatory; Aqueous Humor; Autoimmune Process; Blindness; Cataract; Cell Line; Cells; Chronic; Coupled; Developed Countries; Disease; Dose; Environment; Eye; Eye diseases; Future; Gene Expression; Gene Targeting; Genomic DNA; Glaucoma; Goals; Histology; Human; Immune; Immunohistochemistry; Impairment; In Situ; Infiltration; Inflammation; Inflammatory; Institutes; Interferons; Interleukin-10; Interleukin-17; Lead; Lymphocyte; Measures; Mediating; Messenger RNA; Mission; Modeling; Modification; Mus; National Eye Institute; National Institute of Allergy and Infectious Disease; Oligonucleotides; Patients; Phase; Physicians; Property; Protein Biosynthesis; Research; Risk; Site; Small Business Innovation Research Grant; Steroids; Technology; Therapeutic; Tissues; Transcription Coactivator; Transcriptional Activation; United States National Institutes of Health; Up-Regulation; Uvea; Uveitis; Viral; Vision; base; cytokine; efficacy testing; in vitro Assay; in vivo; mouse model; novel; novel therapeutics; preclinical study; programs; protein expression; public health relevance; therapeutic development; therapeutic target; uveoretinitis

Project Summary Uveitis is an inflammatory disease of the eye that if inadequately treated can lead to vision impairment and blindness. Since the 1950's corticosteroids have been used as the main treatment option despite side effects from prolonged usage in severe and chronic uveitis. Research into uveitis has uncovered its underlying autoimmune mechanisms as facilitated by pathogenic lymphocytes and cytokines. We propose using a novel endogenous transcriptional activation technology to drive specific upregulation of the regulatory cytokine IL-10 to create a tolerogenic immune environment within the eye. The therapeutic development strategy leverages this emerging oligonucleotide-based technology coupled with the proven ameliorating properties of IL-10 in uveitis. Our first aim seeks to refine human and mouse IL-10 transcriptional activators to select for the best candidates. Our second aim builds upon the first by measuring in situ expression of IL-10 as upregulated by our therapeutic in the eyes of mice. Our third aim seeks to demonstrate in vivo efficacy in a mouse model of uveitis by decreasing disease upon treatment by our therapeutics candidates. The overall goal of these studies is to provide proof-of-concept and show efficacy by our novel IL-10 transcriptional activator therapeutic in this Phase I proposal and prepare the project for additional research and pre-clinical studies in Phase II.

项目概要 葡萄膜炎是一种眼部炎症性疾病，如果治疗不当，会导致葡萄膜炎 可导致视力障碍和失明。自 20 世纪 50 年代以来皮质类固醇 尽管长期使用会产生副作用，但仍被用作主要治疗选择 用于严重和慢性葡萄膜炎。对葡萄膜炎的研究揭示了其 致病性淋巴细胞促进的潜在自身免疫机制 和细胞因子。我们建议使用一种新的内源转录激活 驱动调节性细胞因子 IL-10 特异性上调的技术 眼内的耐受性免疫环境。治疗发展 策略利用了这种新兴的基于寡核苷酸的技术以及 IL-10 已被证明可改善葡萄膜炎。我们的首要目标是精益求精 人类和小鼠 IL-10 转录激活剂的最佳选择 候选人。我们的第二个目标建立在第一个目标的基础上，通过测量原位表达 我们的治疗方法在小鼠眼中上调了 IL-10。我们的第三个目标 试图通过减少葡萄膜炎小鼠模型来证明体内功效 我们的候选疗法治疗后出现疾病。这些的总体目标 研究的目的是提供概念验证并展示我们的新型 IL-10 的功效 在这一阶段的建议中转录激活剂治疗并准备 第二阶段的额外研究和临床前研究项目。