IL-23 and IL-17A mRNA-targeted oligonucleotide therapeutics in autoimmune uveitis

IL-23 和 IL-17A mRNA 靶向寡核苷酸治疗自身免疫性葡萄膜炎

• 批准号: 10259979
• 负责人: VINOD Satisch RAMGOLAM
• 金额: $ 31.98万
• 依托单位: TARGETSITE THERAPEUTICS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259979
• 关键词: 3' Untranslated Regions; Adrenal Cortex Hormones; Aqueous Humor; Autoimmune; Autoimmunity; Binding; Binding Proteins; Blindness; Cells; Chemicals; Clinical; Collaborations; Computer Analysis; Cytokine Gene; Data; Development; Disease; Eye diseases; Foundations; Gene Expression; Generations; Histopathology; HuR protein; Immune system; Immunomodulators; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Interleukin-17; Laboratories; Mediating; Messenger RNA; MicroRNAs; Modeling; Mutagenesis; Oligonucleotides; Ophthalmology; Outcome; Pathogenicity; Pharmacotherapy; Phase; Play; Proteins; Public Health; RNA; Rattus; Role; Site; Small Business Innovation Research Grant; Specificity; Testing; Therapeutic; Toxic effect; Transcript; Universities; Uveitis; autoimmune uveitis; base; clinically significant; cytokine; design; drug development; effective therapy; in vivo; innovation; interleukin-23; mRNA Decay; mouse model; novel; novel strategies; novel therapeutic intervention; overexpression; recruit; small molecule; therapeutic target; tool

The pro-inflammatory cytokines IL-23 and IL-17A play critical roles in autoimmune uveitis (AU). Current AU treatments include immunosuppressants, including systemic corticosteroids, accompanied by many challenging toxicities. As a novel cytokine gene expression control mechanism, we found that the microRNA (miRNA) miR466l-3p cooperates with the mRNA- stabilizing protein HuR to augment IL-17A mRNA and protein levels. To exploit this unusual miRNA-mediated enhancing mechanism as a potential therapeutic target, TargetSite Therapeutics and Yale University have collaboratively generated a target site blocker (TSB) oligonucleotide that specifically blocks miR466l-3p binding to the IL-17A 3’UTR, leading to transcript decay and decreased IL-17A protein levels both in vitro and in vivo. This includes our preliminary TSB efficacy data in the rat autoimmune uveitis model. The mRNA levels of IL23, a cytokine upstream of IL-17A, are also augmented in miR466l-overexpressing cells. This Phase I SBIR will provide proof-of-concept that miR466l – cytokine mRNA interaction-specific TSB oligos, either singly or in combination, will be a novel effective treatment for AU. We will do so by: (1) designing, validating and evaluating specificity of a miR466l – IL-23 3’UTR TSB; (2) optimizing the IL-17A mRNA-specific TSB for the foundational (rat) model; and (3) assessing the efficacy of the IL-17A and IL-23 TSBs, singly and in combination, in the rat AU model, by clinical scoring, histopathology and aqueous humor levels of the TSBs and relevant cytokines. The achievable milestone for this Phase I SBIR project is >50% reduction in clinical and histopathologic AU parameters, thereby offering therapeutic benefit of this novel approach in autoimmune uveitis.

促炎细胞因子IL-23和IL-17A在自身免疫性葡萄膜炎（AU）中起关键作用。