microRNA target site RNA-directed oligonucleotide topical therapeutics in psoriasis

摘要 IL-17A/IL-23促炎轴已被确定为有影响力的治疗靶点 银屑病。然而，使用IL-17和IL-23导向的抗体生物制品进行长期的系统治疗可以 免疫抑制，应保留更严重的疾病表现。这 建议重点开发针对IL-17A和IL-23的局部寡核苷酸 成绩单。尽管斑块型牛皮癣存在局部治疗，但其疗效并不显著。一位高度 斑块型银屑病的局部治疗有效地穿透斑块的特定疗法继续 是一个重要的未得到满足的需求。我们的治疗方法是一种新的方法，基于“增强 我们已经开始开发靶点阻滞剂(TSB)的创新平台。 干扰miR4661-3p(MiR466)在单个靶点的增强作用的寡核苷酸 MRNA特异的方式，从而仅抑制该基因的表达。我们已经成功地 产生对IL-17依赖的小鼠高效的IL-17A mRNA特异性TSB 多发性硬化症、自身免疫性葡萄膜炎和局部应用咪喹莫特的免疫/炎症模型 (ImQ)诱导的银屑病。我们的假设是IL-17A和IL-23导向的TSB寡核苷酸，为 高度可穿透性的局部使用，将协同代表一种新颖的、高度特异的、由RNA指导的 治疗牛皮癣。我们组建了一支出色的协作团队，其中包括马克博士 Saltzman是通过纳米颗粒打靶核酸的专家，Jordan Pober博士已经 开发了人到鼠的异种皮肤移植模型。我们的团队现在建议：(1)产生IL-23- 特异性TSB寡核苷酸与体外和体内(ImQ诱导的银屑病)验证，(2)优化 多(胺-酯)(PACE)纳米粒负载IL-23和IL-17A TSB体内测试 (IMQ模型)，以及(3)利用人的皮肤渗透性来确定负载TSB的纳米粒子对人体皮肤的渗透性。 小鼠皮肤异种移植和基于共聚焦成像的穿透分析。这种分子， 临床前模型和生物医学纳米工程有望开发新的治疗方法 斑块型银屑病局部靶向IL-17A/23轴的分子。

Abstract The IL-17A/IL-23 pro-inflammatory axis has been established as an influential therapeutic target in psoriasis. However, long-term systemic treatment with IL-17- and IL-23-directed antibody biologics can be immunosuppressive and should be reserved for the more severe disease manifestations. This proposal is focused on the development of topical oligonucleotides targeting IL-17A and IL-23 transcripts. Although topical treatments for plaque psoriasis exist, their efficacy is modest. A highly specific therapy that effectively penetrates plaques for topical treatment of plaque psoriasis continues to be a significant unmet need. Our therapeutic approach is a novel one, based on an "enhancing microRNA" mechanism. We have begun developing an innovative platform of target site blocker (TSB) oligonucleotides that interfere with the enhancing effect of miR466l-3p (miR466) in an individual target mRNA-specific fashion, thereby repressing expression of only that gene. We have successfully generated an IL-17A mRNA-specific TSB that is highly effective in IL-17-dependent murine immune/inflammatory models of multiple sclerosis, autoimmune uveitis, and topically in imiquimod (IMQ)- induced psoriasis. Our hypothesis that IL-17A- and IL-23- directed TSB oligos, formulated for highly penetrable topical use, will synergistically represent a novel, highly specific, RNA-directed treatment in psoriasis. We have assembled an outstanding collaborative team, which includes Dr. Mark Saltzman, an expert in nucleic acid targeting through nanoparticles, and Dr. Jordan Pober, who has developed human-to-mouse skin xenograft models. Our team now proposes to: (1) generate an IL-23- specific TSB oligonucleotide with in vitro and in vivo (IMQ-induced psoriasis) validation, (2) optimize poly(amine-co-ester) (PACE) nanoparticle (NP)-loaded IL-23 and IL-17A TSBs, with testing in vivo (IMQ model), and (3) determine the penetrability of the TSB-loaded NPs into human skin, using human- to-mouse skin xenografting and confocal imaging-based penetration analysis. This molecular, preclinical model and biomedical nanoparticle engineering promises to develop novel therapeutic molecules for topical targeting of the IL-17A/23 axis in plaque psoriasis.