The roots of SLE: Can we cure it with a reverse transcriptase inhibitor?

SLE 的根源：我们可以用逆转录酶抑制剂治愈它吗？

• 批准号: 9922870
• 负责人: Tomas M Mustelin
• 金额: $ 19.42万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922870
• 关键词: Address; Adult; Agreement; Applications Grants; Autoantibodies; Automobile Driving; B-Lymphocytes; Biological Assay; Biological Markers; Blocking Antibodies; CD28 gene; CTLA4-Ig; Calcineurin inhibitor; Cell Line; Cells; Clinical; Clinical Trials; DNA; Data; Dendritic Cells; Dermatomyositis; Development; Disease; Dose; Elements; Etiology; FDA approved; Flare; Funding; Future; Genetic Transcription; Goals; Grant; HIV; HL60; Human; Hydroxychloroquine; IFNAR1 gene; IRF3 gene; Immune; Immune system; Immunosuppression; In Vitro; Interferon Receptor; Interferon Type I; Interferons; Leukocytes; Lupus Nephritis; Lymphocyte; Measures; Messenger RNA; Mixed Connective Tissue Disease; Molecular; Nuclear; Outcome; Paper; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phenotype; Physiology; Placebos; Plant Roots; Play; Production; Proteins; Publishing; RNA Binding; RNA-Directed DNA Polymerase; Regimen; Research; Reverse Transcriptase Inhibitors; Role; Safety; Signs and Symptoms; Sjogren' s Syndrome; Stimulator of Interferon Genes; Systemic Lupus Erythematosus; T-Lymphocyte; TLR7 gene; Tenofovir; Testing; Therapeutic; Work; base; belimumab; cell type; drug market; emtricitabine; experimental study; granulocyte; healthy volunteer; improved; in vitro activity; indexing; inhibitor/antagonist; insight; mortality; neutralizing monoclonal antibodies; neutrophil; new therapeutic target; novel; patient safety; prevent; research clinical testing; sensor; side effect; targeted treatment; tositumomab

Project Summary/Abstract Systemic lupus erythematosus (SLE) is a challenging disease with a significant mortality. Unfortunately, existing treatments have limited efficacy and/or serious side-effects, including the consequences of broad suppression of the immune system. A long-term goal of this research is to improve mankind's understanding of the underlying molecular drivers and mechanisms of SLE to enable the development new and better therapies that address this core pathobiology but spare the broader immune system. This grant addresses the novel hypothesis that long interspersed nuclear elements (LINE1) are the core driver of SLE. They are transcriptionally activated in SLE patients, as well as in closely related diseases like Sjögren's syndrome, and encode for two proteins, the RNA-binding p40/ORF1 and the 150-kDa ORF2 reverse transcriptase (RT), which can generate DNA using LINE1 mRNA, or other mRNAs, as a template. The resulting DNA triggers the cGAS - STING pathway to induce interferon (IFN)  and/or  (depending on cell type), which, in turn, appear to play a critical role in driving SLE, as demonstrated by phase 2 efficacy of the type I IFN receptor (IFNAR1)-blocking antibody anifrolumab. In contrast, mAbs neutralizing IFN alone had much lower efficacy, suggesting that INF is also important. In agreement with this notion, blocking INF production by plasmacytoid dendritic cells (pDC) with TLR7 and 9 antagonists have so far failed in clinical trials in SLE. Instead, there is recent evidence that the cGAS - STING pathway is activated in SLE patients. Aims of the research plan are: SPECIFIC AIM 1: To verify the LINE1 RT - IRF3 - IFN axis in SLE patients. SPECIFIC AIM 2. To block the LINE1 - IRF3 - IFN pathway with RTi. Experiments will verify that this pathway occurs in SLE patients, identify measures (biomarkers) that can be used in a clinical trial, validate the RT as a drug target for the treatment of human SLE, and establish the rationale for future clinical testing. The therapeutic implication of this work is that inhibition of the LINE1 RT may halt early SLE as well as prevent new flares in established disease. Since the LINE1 RT does not have any known functions in healthy adult physiology, it appears that inhibiting LINE1 RT would be well tolerated. Indeed, two published papers indicate that several clinically used HIV RT inhibitors also inhibit LINE1 RT, including some of the most recent drugs like emtricitabine and tenofovir alafenamide, which have a particularly good safety record.

项目概要/摘要 系统性红斑狼疮（SLE）是一种具有挑战性的疾病，死亡率很高。 不幸的是，现有的治疗方法疗效有限和/或有严重的副作用，包括 免疫系统广泛抑制的后果。 这项研究的长期目标是提高人类对底层的理解 SLE 的分子驱动因素和机制，有助于开发新的更好的疗法 解决这一核心病理学问题，但不影响更广泛的免疫系统。这笔赠款地址 长散布核元件 (LINE1) 是 SLE 的核心驱动因素的新假设。 它们在 SLE 患者以及密切相关的疾病（如 干燥综合征，编码两种蛋白质：RNA 结合 p40/ORF1 和 150-kDa ORF2 逆转录酶 (RT)，可以使用 LINE1 mRNA 或其他 mRNA 生成 DNA， 作为模板。由此产生的 DNA 触发 cGAS - STING 通路以诱导干扰素 (IFN)  和/或 （取决于细胞类型），反过来，它们似乎在驱动 SLE 中发挥着关键作用， I 型 IFN 受体 (IFNAR1) 阻断抗体的 2 期疗效证明 阿尼福鲁单抗。相比之下，单独中和 IFNα 的单克隆抗体的功效要低得多，这表明 INF也很重要。与此观点一致，通过类浆细胞阻断 INFα 的产生 迄今为止，使用 TLR7 和 9 拮抗剂的树突状细胞 (pDC) 在 SLE 临床试验中均失败。 相反，最近有证据表明 cGAS - STING 通路在 SLE 患者中被激活。 研究计划的目标是： 具体目标 1：验证 SLE 患者的 LINE1 RT - IRF3 - IFN 轴。 具体目标 2. 用 RTi 阻断 LINE1 - IRF3 - IFN 途径。 实验将验证该途径是否发生在 SLE 患者中，确定措施（生物标志物） 可用于临床试验，验证 RT 作为治疗人类的药物靶点 SLE，并为未来的临床测试奠定基础。 这项工作的治疗意义是抑制 LINE1 RT 可能会阻止早期 SLE 以及预防已确定疾病的新发作。由于 LINE1 RT 没有任何已知的 LINE1 RT 在健康成人生理学中发挥作用，抑制 LINE1 RT 似乎具有良好的耐受性。 事实上，两篇发表的论文表明，几种临床使用的 HIV RT 抑制剂也抑制 LINE1 RT，包括一些最新的药物，如恩曲他滨和替诺福韦艾拉酚胺， 拥有特别良好的安全记录。