Selective induction of endogenous IL10 for the treatment of uveitis

项目摘要 葡萄膜炎是一种炎症性疾病的眼睛，如果治疗不当， 会导致视力受损和失明。自20世纪50年代以来，皮质类固醇 已被用作主要的治疗选择，尽管长期的副作用 用于严重和慢性葡萄膜炎。对葡萄膜炎的研究发现， 病原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性转录激活 技术来驱动调节细胞因子IL-10的特异性上调， 眼内的致耐受性免疫环境。治疗发展 该战略利用了这种新兴的基于磷脂的技术， IL-10在葡萄膜炎中的已证实的改善特性。我们的首要目标是 人和小鼠IL-10转录激活因子以选择最佳 候选人我们的第二个目标建立在第一个基础上，通过测量原位表达， IL-10在小鼠眼中被我们的治疗剂上调。我们的第三个目标 试图证明在葡萄膜炎的小鼠模型中的体内功效， 我们的候选治疗药物治疗后的疾病。这些活动的总体目标 研究的目的是提供概念验证，并显示我们的新型IL-10的疗效 转录激活剂治疗在这个阶段I的建议，并准备 II期额外研究和临床前研究项目。

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.