IL-23 and IL-17A mRNA-targeted oligonucleotide therapeutics in autoimmune uveitis

促炎细胞因子IL-23和IL-17 A在自身免疫性葡萄膜炎（Au）中起关键作用。 目前的Au治疗包括免疫抑制剂，包括全身性皮质类固醇， 伴随着许多具有挑战性的毒性。作为一种新型的细胞因子基因表达调控 机制，我们发现microRNA（miRNA）miR 466 l-3 p与mRNA- 稳定蛋白HuR以增加IL-17 A mRNA和蛋白水平。利用这个不寻常的 miRNA介导的增强机制作为潜在的治疗靶点，TargetSite Therapeutics和耶鲁大学合作开发了一种靶点阻滞剂（TSB） 特异性阻断miR 466 l-3 p与IL-17 A 3 'UTR结合的寡核苷酸，导致 在体外和体内，IL-17 A转录物衰减和降低的IL-17 A蛋白水平。这包括我们 在大鼠自身免疫性葡萄膜炎模型中的初步TSB功效数据。IL 23、a IL-17 A上游的细胞因子的表达也在miR 466 l过表达细胞中增加。这个阶段 I SBIR将提供miR 466 l-细胞因子mRNA相互作用特异性TSB的概念验证 寡聚物，无论是单独或组合，将是一种新的有效的治疗Au。我们将这样做 通过：（1）设计、验证和评估miR 4661- IL-23 3 'UTR TSB的特异性; (2)优化基础（大鼠）模型的IL-17 A mRNA特异性TSB;和（3） 评估IL-17 A和IL-23 TSB单独和组合在大鼠Au中的功效 通过临床评分、组织病理学和TSB的房水水平以及相关的 细胞因子本SBIR项目I期可实现的里程碑是临床试验减少>50%。 和组织病理学Au参数，从而提供这种新方法的治疗益处 自身免疫性葡萄膜炎

The pro-inflammatory cytokines IL-23 and IL-17A play critical roles in autoimmune uveitis (AU). Current AU treatments include immunosuppressants, including systemic corticosteroids, accompanied by many challenging toxicities. As a novel cytokine gene expression control mechanism, we found that the microRNA (miRNA) miR466l-3p cooperates with the mRNA- stabilizing protein HuR to augment IL-17A mRNA and protein levels. To exploit this unusual miRNA-mediated enhancing mechanism as a potential therapeutic target, TargetSite Therapeutics and Yale University have collaboratively generated a target site blocker (TSB) oligonucleotide that specifically blocks miR466l-3p binding to the IL-17A 3’UTR, leading to transcript decay and decreased IL-17A protein levels both in vitro and in vivo. This includes our preliminary TSB efficacy data in the rat autoimmune uveitis model. The mRNA levels of IL23, a cytokine upstream of IL-17A, are also augmented in miR466l-overexpressing cells. This Phase I SBIR will provide proof-of-concept that miR466l – cytokine mRNA interaction-specific TSB oligos, either singly or in combination, will be a novel effective treatment for AU. We will do so by: (1) designing, validating and evaluating specificity of a miR466l – IL-23 3’UTR TSB; (2) optimizing the IL-17A mRNA-specific TSB for the foundational (rat) model; and (3) assessing the efficacy of the IL-17A and IL-23 TSBs, singly and in combination, in the rat AU model, by clinical scoring, histopathology and aqueous humor levels of the TSBs and relevant cytokines. The achievable milestone for this Phase I SBIR project is >50% reduction in clinical and histopathologic AU parameters, thereby offering therapeutic benefit of this novel approach in autoimmune uveitis.