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：
10287633
负责人：
JEFFREY R. BENDER
金额：
$ 22.11万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10287633
关键词：
3&apos Untranslated Regions Amines Anti-Inflammatory Agents Antibodies Artificial nanoparticles Autoimmune Diseases Autoimmunity Binding Biological 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促炎轴已被确立为有影响力的治疗靶点银屑病。然而，使用 IL-17 和 IL-23 导向的抗体生物制剂进行长期全身治疗可以具有免疫抑制作用，应保留用于更严重的疾病表现。这该提案的重点是开发针对 IL-17A 和 IL-23 的局部寡核苷酸成绩单。尽管存在斑块状银屑病的局部治疗，但其疗效有限。一个高度有效渗透斑块以局部治疗斑块型银屑病的特定疗法仍在继续是一个重大的未满足的需求。我们的治疗方法是一种新颖的方法，基于“增强 microRNA”机制。我们已经开始开发靶点阻断剂（TSB）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 特异性方式，从而仅抑制该基因的表达。我们已经成功产生了 IL-17A mRNA 特异性 TSB，对 IL-17 依赖性小鼠非常有效多发性硬化症、自身免疫性葡萄膜炎和局部咪喹莫特的免疫/炎症模型 (IMQ)-诱发牛皮癣。我们的假设是，IL-17A 和 IL-23 导向的 TSB 寡核苷酸，配制用于高度渗透的局部使用，将协同代表一种新颖的、高度特异性的、RNA 导向的牛皮癣的治疗。我们组建了一支优秀的协作团队，其中包括马克博士 Saltzman 是纳米粒子核酸靶向领域的专家，Jordan Pober 博士是开发了人鼠皮肤异种移植模型。我们的团队现在建议：（1）生成 IL-23- 具有体外和体内（IMQ 诱导的牛皮癣）验证的特定 TSB 寡核苷酸，(2) 优化负载聚胺酯 (PACE) 纳米颗粒 (NP) 的 IL-23 和 IL-17A TSB，经过体内测试（IMQ 模型），以及（3）使用人体模型确定负载 TSB 的纳米颗粒对人体皮肤的渗透性。小鼠皮肤异种移植和基于共焦成像的渗透分析。这个分子，临床前模型和生物医学纳米颗粒工程有望开发新的治疗方法斑块状银屑病中局部靶向 IL-17A/23 轴的分子。