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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.

摘要