IL-17A mRNA-targeted oligonucleotide therapeutics in Idiopathic Pulmonary Fibrosis (IPF)

抽象的。特发性肺纤维化是一种进行性纤维增生性疾病，影响300万∼。 全球范围内有功能受限进行性症状且中位生存期为2-3年的患者 诊断。虽然IPF的病因尚不清楚，但遗传因素、环境暴露和微生物 病原体已被确定为IPF的危险因素。吡非尼酮和九替达尼目前是两种口服药物 注射了纤维化抑制药。然而，两者都伴随着广泛的不良反应，限制了用途。 因此，存在对可耐受和有效的治疗选择的高度未得到满足的需求。基于一项在 学术合作伙伴耶鲁大学实验室TargetSite治疗公司正在开发一种新型的 选择性干扰“增强型”结合相互作用的寡核苷酸治疗药物 MicroRNA“(e-miRNA)，miR466l-3p，与mRNA的3‘非编码区内的特定靶点结合。这些“目标站点屏蔽” (TSB)寡核苷酸有效和特异地干扰单个促炎因子的产生 细胞因子和生长因子包括IL-17A、IL-22、GM-CSF、IL-23A、血管内皮生长因子A和IL-1β。IL-17A一直是 据报道，IPF患者的支气管肺泡灌洗液(BAL)中显著升高。因此，我们 建议用特异性TSB靶向IL-17A mRNA，并评估其在已建立的博莱霉素瘤模型中的疗效。 诱导肺纤维化(IPF)模型。将与Matinas Biophma合作，尝试将 IL-17A TSB在多层脂质纳米晶中，这是口服给药优化。我们将验证 这些TSB-LNC在体外对Th17细胞的作用及其降低内毒素诱导的IL-2的生物活性 17A在小鼠体内。LNC包裹和裸(PBS)IL-17A TSB寡核苷酸的有效性将通过以下两种方法进行测试 在博莱霉素诱导的小鼠肺间质纤维化模型中，通过腹腔和口服(通过灌胃)给药。初级评估 参数将是肺纤维化，组织病理学和生化，以及BAL液和血清IL-17A 级别。疾病严重性的降低，由可量化的纤维化减少50%来确定，预计为 这是一个可以实现的里程碑，也是一个可以定义的成功标准。这个项目的实验证据将 确认IL-17mRNA导向的寡核苷酸是否有益地改变了疾病，提供了一种新的治疗方法 治疗特发性肺间质纤维化。

Abstract. Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder affecting ∼3 million people worldwide with function-limiting progressive symptoms and a 2-3 year median survival time from diagnosis. While the etiology of IPF is not clear, genetic factors, environmental exposures and microbial pathogens have been identified as IPF risk factors. Pirfenidone and nintedanib currently are two orally administrated fibrosis inhibitors. However, both are accompanied by a wide adverse effect profile, limiting utility. Thus, a high unmet need exists for tolerable and effective treatment options. Based on a discovery in the academic partner Yale university laboratory, TargetSite Therapeutics Corporation is developing a novel class of oligonucleotide therapeutic agents that selectively interfere with the binding interaction of an “enhancing microRNA” (e-miRNA), miR466l-3p, to specific target sites within an mRNA’s 3’UTR. These “target site blocking” (TSB) oligonucleotides effectively and specifically interfere with the production of individual pro-inflammatory cytokines and growth factors including IL-17A, IL-22, GM-CSF, IL-23A, VEGF-A and IL-1β. IL-17A has been reported to be significantly elevated in the bronchoalveolar lavage (BAL) fluid of IPF patients. We therefore propose targeting the IL-17A mRNA with a specific TSB and assess its efficacy in the established bleomycin- induced lung fibrosis (IPF) model. In partnership with Matinas Biopharma, attempts will be made to encapsulate the IL-17A TSB in multilayered lipid nanocrystals, which are optimized for oral delivery. We will validate the efficacy of these TSB-LNC in Th17 cells in vitro, and for their biological activity in reduction of LPS-induced IL- 17A in mice. The efficacy of LNC-encapsulated and naked (PBS) IL-17A TSB oligos will be tested, both by intraperitoneal and oral (via gavage) delivery, in the bleomycin-induced murine IPF model. Primary assessment parameters will be lung fibrosis, histopathological and biochemically, as well as BAL fluid and serum IL-17A levels. A reduction in disease severity, as determined by >50% reduction in quantifiable fibrosis, is expected as an achievable milestone and a definable criterion for success. Experimental evidence from this project will confirm whether the IL-17 mRNA-directed oligos beneficially modify the disease, providing a novel therapeutic in the treatment of IPF.