mTOR Regulation of Basal Antiviral Immunity in the Elderly

摘要 鉴于老年人COVID-19感染的死亡率升高（Wu et al 2020）， 迫切需要评估可能预防这些脆弱人群严重疾病的药物， 患者抑制雷帕霉素复合物1（TORC 1）靶点下游的靶点。 据报道，上调泛抗病毒基因的表达，并保护小鼠免受病毒性呼吸道感染。 肠道感染（RTI）（约克AG等人，2015）。重要的是，还观察到RTB 101 上调干扰素刺激的泛抗病毒基因表达， 血清中的炎性细胞因子，并降低病毒性呼吸道疾病的发生率和严重程度， 在冬季寒冷期间预防包括冠状病毒感染在内的肠道感染 和流感季节对老年人的影响（Mannick等人，2018年，Mannick等人，2019年）。因此我们 假设RTB 101将降低COVID-19的发病率和严重程度， 预防老年人。在对该适应症进行大型有效性试验之前，我们 建议进行一项试点研究，以确定招募，同意， 筛选和随机化被隔离的老年人门诊人群， 发展为COVID-19的风险增加（具体目标1），评估COVID-19是否 可以使用老年人的电子日志（具体目标2）跟踪症状，并获得 接受RTB 101治疗的受试者中COVID-19发病率和严重程度的初步数据， 与安慰剂相比（具体目标3）。试验中产生的数据将用于帮助 优化一项更大规模的充分把握度研究的研究设计，以确定RTB 101是否 对老年人有效的COVID-19预防。 引用 1. Mannick，J. B.，Morris M，Hockey HP，Roma G，Beibel M，Kulmatycki K等人（2018） TORC 1抑制增强免疫功能并减少老年人的感染。Sci Transl Med 10，doi：10.1126/scitranslmed.aaq1564。 2. Mannick et al，（摘要）IDWeek，2019。 3.作者声明：J.冠状病毒的特征和重要教训 2019年中国新冠肺炎疫情：72314例报告总结 来自中国疾病预防控制中心。JAMA. 2020年2月24日。 4.约克AG，威廉姆斯KJ，阿格斯JP，周QD，Brar G，等.（2015） 限制胆固醇生物合成流量赞助商参与I型干扰素信号传导。 Cell. 163（7）：1716-29。

Abstract Given the elevated mortality of COVID-19 infections in older adults (Wu et al 2020), there is an urgent need to evaluate medicines that may prevent severe disease in these vulnerable patients. Inhibition of targets downstream of target of rapamycin complex 1 (TORC1) was reported to upregulate pan-antiviral gene expression and protect mice from a viral respiratory tract infection (RTI) (York AG et al. 2015). Importantly, RTB101 was also observed to upregulate interferon-stimulated pan-antiviral gene expression, decrease the levels of inflammatory cytokines in serum, and decrease the incidence and severity of viral respiratory tract infections including coronavirus infections when given as prophylaxis during winter cold and flu season to older adults (Mannick et al. 2018, Mannick et al., 2019). Therefore we hypothesize that RTB101 will decrease the incidence and severity of COVID-19 when given as prophylaxis to older adults. Before undertaking a large well-powered trial for this indication, we propose to undertake a pilot study to determine the feasibility of recruiting, consenting, screening and randomizing quarantined outpatient populations of older adults who are predicted to be at increased risk of developing COVID-19 (Specific Aim 1), assess whether COVID-19 symptoms can be tracked using an eDiary in older adults (Specific Aim 2), and obtain preliminary data on the incidence and severity of COVID-19 in subjects treated with RTB101 as compared to placebo (Specific Aim 3). The data generated in the trial will be used to help optimize the study design of a larger adequately powered study to determine if RTB101 is effective as COVID-19 prophylaxis in the older adults. References 1. Mannick, J. B., Morris M, Hockey HP, Roma G, Beibel M, Kulmatycki K et al. (2018) TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med 10, doi:10.1126/scitranslmed.aaq1564. 2. Mannick et al, (abstract) IDWeek, 2019. 3. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Feb 24. 4. York AG, Williams KJ, Argus JP, Zhou QD, Brar G, et al. (2015) Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling. Cell. 163(7):1716-29.