Development of TLR8 inhibitors for treatment of autoimmune diseases

描述（由申请人提供）：当适应性免疫反应靶向自身抗原时，发生自身免疫性疾病，导致炎症和组织破坏。先天性免疫系统面临着与适应性免疫系统相同的基本挑战-区分自身抗原和非自身抗原-现在有相当多的证据表明，通过Toll样受体（TLR）识别自身核酸可以显着促进无菌炎症和自身免疫，最明显的例子是TLR 9和TLR 7在系统性红斑狼疮（SLE）发病机制中所起的作用。主要的例外是TLR 8，尽管其能够刺激重要的炎性细胞因子如IL 6和TNF-1，并且其通过参与炎性疾病的多种细胞类型表达。由于人TLR 8和其啮齿动物直系同源物的非常不同的配体特异性，缺乏有用的动物啮齿动物模型已被证明是TLR 8生物学研究中的主要限制。小鼠TLR 8缺乏响应ssRNA配体、RNA病毒或小分子的能力;所有这些都已被证明能激活人TLR 8。我们已经开发了新的工具，我们希望这将有助于更好地了解TLR 8的生物学。因此，本提案的主要目的是鉴定和表征适用于IND使能临床前和工艺开发研究的前导TLR 8抑制性寡核苷酸。主要活动将包括：“使用人原代细胞体外试验鉴定基于阿托西肽的人TLR 8抑制剂“，确定其对其他TLR途径的特异性，“在急性模型中测试其体内活性“，确定其预防啮齿动物中TLR 8依赖性自身免疫疾病的能力。如果成功，所产生的数据将为TLR 8抑制剂用于自身免疫性疾病的全面开发计划提供基础。

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.