microRNA target site RNA-directed oligonucleotide topical therapeutics in psoriasis

microRNA 靶位点 RNA 引导的寡核苷酸局部治疗银屑病

基本信息

批准号：
10426347
负责人：
JEFFREY R. BENDER
金额：
$ 18.24万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10426347
关键词：
3&apos Untranslated Regions Amines Anti-Inflammatory Agents Antibodies Artificial nanoparticles Autoimmune Diseases Autoimmunity Binding Biological Products Chronic small plaque psoriasis Cutaneous DNA Development Disease Esters Fluorochrome Formulation Gene Expression Generations Genes Genetic Materials Goals Human Imiquimod Immune Immune system In Vitro Individual Inflammatory Influentials Interleukin-17 Interleukins Jordan Label Mediating Messenger RNA MicroRNAs Modeling Molecular Molecular Target Multiple Sclerosis Mus Nucleic Acids Oligonucleotides Pathogenicity Penetration Play Polymers Pre-Clinical Model Production Proteins Psoriasis RNA Role Site Skin System Therapeutic Topical application Toxic effect Transcript Validation Xenograft Model autoimmune uveitis base confocal imaging cytokine design detection assay drug development gene product in vivo in vivo evaluation innovation interleukin-23 mouse model nanoparticle novel novel drug class novel therapeutics particle recruit skin xenograft therapeutic target

项目摘要

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.

抽象的 IL-17A/IL-23促炎轴已被确定为有影响力的治疗靶标银屑病。但是，用IL-17-和IL-23定向抗体生物制剂的长期全身治疗可以进行免疫抑制，应保留给更严重的疾病表现。这提案的重点是针对IL-17A和IL-23的局部寡核苷酸的发展成绩单。尽管存在有关斑块牛皮癣的局部治疗方法，但其功效是适度的。高度有效地穿透斑块用于局部治疗斑块牛皮癣的特定疗法继续是一个很大的未满足需求。我们的治疗方法是一种新颖的方法，基于“增强 MicroRNA“机制。我们已经开始开发目标站点阻滞剂（TSB）的创新平台干扰MiR466L-3P（miR466）在单个靶标中的增强作用的寡核苷酸 mRNA特异性的时尚，从而仅抑制该基因的表达。我们已经成功产生的IL-17a mRNA特异性TSB在IL-17依赖性鼠中非常有效多发性硬化症，自身免疫性葡萄膜炎的免疫/炎症模型以及局部（IMQ） - 诱导牛皮癣。我们的假设是IL-17A-和IL-23-定向的TSB寡聚，为高度渗透的局部用途，将协同代表一种新颖的，高度特异性的RNA指导牛皮癣的治疗。我们组建了一个杰出的合作团队，其中包括马克博士。萨尔茨曼（Saltzman 开发了人类对小鼠皮肤异种移植模型。我们的团队现在建议：（1）生成IL-23-- 特异性TSB寡核苷酸具有体外和体内（IMQ诱导的牛皮癣）验证，（2）优化 poly（氨基酯）（PACE）纳米颗粒（NP）负载的IL-23和IL-17A TSB，并在体内进行测试（IMQ模型）和（3）使用人类确定了TSB加载的NP的渗透性结合皮肤异种和共聚焦成像的渗透分析。这个分子，临床前模型和生物医学纳米颗粒工程有望发展出新的治疗性用于斑块牛皮癣中IL-17A/23轴局部靶向的分子。