Development of TLR8 inhibitors for treatment of autoimmune diseases

开发用于治疗自身免疫性疾病的TLR8抑制剂

• 批准号: 8472437
• 负责人: Cristiana Guiducci
• 金额: $ 29.95万
• 依托单位: DYNAVAX TECHNOLOGIES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8472437
• 关键词: Acute; Animals; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biology; Blood; Blood Cells; Cells; Data; Dendritic Cells; Development; Disease; Disease model; Dose; Drug Targeting; Evaluation; Face; Frequencies; Genetic Polymorphism; Government; Human; IL6 gene; IL8 gene; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin-12; Interleukin-6; Lead; Ligands; Modeling; Mus; Myelogenous; Nucleic Acids; Oligonucleotides; Organ; Orthologous Gene; Pathogenesis; Persons; Pharmaceutical Preparations; Pharmacodynamics; Play; Process; Production; Program Development; RNA; RNA Viruses; Rheumatoid Arthritis; Rodent; Rodent Model; Role; Specificity; Splenocyte; Sterility; Symptoms; Systemic Lupus Erythematosus; TLR7 gene; TLR8 gene; TNF gene; Testing; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Transgenic Mice; Variant; base; cell type; counterscreen; cytokine; human TLR7 protein; human TLR8 protein; in vitro Assay; in vivo; inhibitor/antagonist; insight; macrophage; monocyte; mouse model; neutrophil; novel; pre-clinical; prevent; promoter; receptor; research study; response; screening; small molecule; tool; tool development

DESCRIPTION (provided by applicant): Autoimmune diseases develop when the adaptive immune response targets self-antigens, leading to inflammation and tissue destruction. The innate immune system faces the same fundamental challenge as the adaptive immune system - distinguishing self from non-self antigens - and there is now considerable evidence that recognition of self nucleic acids through toll-like receptors (TLRs) can contribute significantly to sterile inflammation and autoimmunity, with the clearest example being the role played by TLR9 and TLR7 in the pathogenesis of systemic lupus erythematosus (SLE). The major exception has been TLR8, despite its ability to stimulate important inflammatory cytokines such as IL6 and TNF-1, and its expression by multiple cell types involved in inflammatory diseases. The lack of useful animal rodent models, a consequence of the very different ligand specificity of human TLR8 and its rodent orthologs, has proven to be a major limitation in the study of TLR8 biology. Mouse TLR8 lacks the capability of responding to ssRNA ligands, RNA viruses, or small molecules; all of which have been shown to activate human TLR8. We have developed new tools that we hope will help better understand the biology of TLR8. The key objective of this proposal is thus to identify and characterize a lead TLR8 inhibitory oligonucleotide suitable for IND-enabling preclinical and process-development studies. The principal activities will include: " Identify an oligonucleotide-based inhibitor of human TLR8 using in vitro assays with human primary cells, " Define its specificity against the other TLR pathways, " Test its activity in vivo in an acute model, " Determine its ability to prevent a TLR8-dependent autoimmune disease in rodents. If successful, the data generated will provide the groundwork for a full-scale development program for a TLR8 inhibitor for autoimmune diseases.

描述(申请人提供)：当适应性免疫反应以自身抗原为目标，导致炎症和组织破坏时，自身免疫性疾病就会发生。天然免疫系统面临着与适应性免疫系统相同的根本挑战-区分自身和非自身抗原-现在有相当多的证据表明，通过Toll样受体(Toll样受体)识别自身核酸可以显著促进无菌炎症和自身免疫，最明显的例子是TLR9和TLR7在系统性红斑狼疮(SLE)的发病机制中所起的作用。主要的例外是TLR8，尽管它能够刺激重要的炎性细胞因子，如IL6和TNF-1，并由参与炎症性疾病的多种细胞类型表达。由于人类TLR8及其同源基因的配基特异性不同，缺乏实用的动物啮齿动物模型已被证明是TLR8生物学研究的主要限制。小鼠TLR8缺乏对单链RNA配体、RNA病毒或小分子的反应能力；所有这些都已被证明能激活人类TLR8。我们已经开发了新的工具，我们希望这些工具将有助于更好地了解TLR8的生物学。因此，这项建议的关键目标是确定和表征一种适合于IND使能临床前和过程开发研究的先导TLR8抑制寡核苷酸。主要活动将包括：“使用人类原代细胞的体外分析鉴定一种基于寡核苷酸的人TLR8抑制剂”，确定其相对于其他TLR途径的特异性，“在急性模型中测试其体内活性”，确定其预防啮齿类动物TLR8依赖的自身免疫性疾病的能力。如果成功，产生的数据将为针对自身免疫性疾病的TLR8抑制剂的全面开发计划奠定基础。