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

项目总结/摘要 系统性红斑狼疮（SLE）是一种具有挑战性的疾病，具有显着的死亡率。 不幸的是，现有的治疗具有有限的功效和/或严重的副作用，包括 免疫系统受到广泛抑制的后果。 这项研究的一个长期目标是提高人类对 SLE的分子驱动因素和机制，以开发新的更好的治疗方法 解决这个核心病理学问题，但不影响更广泛的免疫系统。该补助金涉及 新的假说，即长散布核元件（LINE 1）是SLE的核心驱动力。 它们在SLE患者以及密切相关的疾病中被转录激活， Sjögren综合征，并编码两种蛋白质，RNA结合p40/ORF 1和150-kDa ORF 2逆转录酶（RT），其可以使用LINE 1 mRNA或其他mRNA产生DNA， 作为模板。产生的DNA触发cGAS-STING途径以诱导干扰素（IFN） α和/或β（取决于细胞类型），其反过来似乎在驱动SLE中起关键作用， 如I型IFN受体（IFNAR 1）阻断抗体的2期疗效所证明的 阿尼福鲁单抗。相比之下，单独中和IFN γ的mAb具有低得多的功效，表明 INF也很重要。与这一观点一致，阻断类浆细胞产生INF β， 具有TLR 7和TLR 9拮抗剂的树突细胞（pDC）迄今在SLE的临床试验中失败。 相反，最近有证据表明cGAS-STING途径在SLE患者中被激活。 研究计划的目的是： 具体目的1：验证SLE患者LINE 1 RT-IRF 3- IFN轴的表达. 具体目标2.用RTi阻断LINE 1-IRF 3- IFN途径。 实验将验证这一途径发生在SLE患者，确定措施（生物标志物） 可以用于临床试验，验证RT作为治疗人类肿瘤的药物靶标。 SLE，并建立未来临床试验的依据。 这项工作的治疗意义是，抑制LINE 1 RT可以阻止早期SLE， 也能防止已经存在的疾病再次爆发。由于LINE 1 RT没有任何已知的 在健康成人生理学中，似乎抑制LINE 1 RT将是良好耐受的。 事实上，两篇发表的论文表明，几种临床使用的HIV RT抑制剂也抑制了 LINE 1 RT，包括一些最新的药物，如恩曲他滨和替诺福韦艾拉酚胺， 有着特别好的安全记录。

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.