Pre-clinical assessment of JAK inhibitors to ameliorate cytokine storms in Down syndrome

JAK 抑制剂改善唐氏综合症细胞因子风暴的临床前评估

• 批准号: 10163708
• 负责人: Kelly D. Sullivan
• 金额: $ 25.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163708
• 关键词: 2019-nCoV; Administrative Supplement; Adult Respiratory Distress Syndrome; Agonist; Animal Model; Antiviral Agents; Attenuated; Award; Biodistribution; Biological Models; Blood; CCL2 gene; COVID-19; CXCL10 gene; Cessation of life; Chromosome 21; Chronic; Clinical Data; Clinical Trials; Clinical assessments; Data; Down Syndrome; Exhibits; FDA approved; Follow-Up Studies; Healthcare Systems; Heart; Heart failure; Histologic; Hypersensitivity; Immune; Immune response; Immunization; Immunological Models; Individual; Infection; Inflammation; Interferon Activation; Interferon Receptor; Interferons; JAK1 gene; JAK2 gene; JAK3 gene; Janus kinase; Link; Liver; Lung; Modeling; Molecular; Morbidity - disease rate; Mus; Organ; Outcome; Parents; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Phosphotransferases; Plasma; Poly C; Poly I-C; Preclinical Testing; Production; Property; Proteome; Research Design; Role; Savings; Signal Transduction; Specificity; Symptoms; TLR3 gene; TYK2; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; associated symptom; combat; cytokine; cytokine release syndrome; experience; high risk population; inhibitor/antagonist; kinase inhibitor; liver injury; medical countermeasure; mouse model; novel vaccines; outcome forecast; pandemic disease; pre-clinical; response; symptom treatment; vaccine evaluation

ABSTRACT. This application is being submitted to PA-18-591 in accordance with NOT-AI-20-031. The recent emergence of SARS-CoV-2 and COVID-19 has created an urgent need for rapid deployment of therapeutic strategies to combat the current pandemic, and major efforts are underway to develop new vaccines and antiviral medications, however, results from these efforts are not expected in the near term. A more immediate approach is to repurpose existing therapeutics approved by the FDA for other conditions to remediate symptoms associated with the most severe COVID-19 outcomes, potentially saving lives and reducing the burden on the healthcare system. Within this framework, cytokine release syndrome (CRS) also known as cytokine storm or hypercytokinemia, has been implicated in acute respiratory distress syndrome, heart failure, and death in patients with COVID-19 (1-5). However, although diverse immune-suppressive strategies to attenuate the cytokine storm are being tested in clinical trials for COVID-19, there is a dearth of pre-clinical data supporting their use to attenuate cytokine-driven pathology. Therefore, we propose here to test the ability of FDA-approved inhibitors of Janus Kinases (JAKs) to mitigate rampant cytokine production and multi-organ inflammation in a mouse model of non-infectious lethal immune hypersensitivity. This mouse model has arisen directly from our work over the past five years that revealed a major role for immune dysregulation in Down syndrome (DS). We demonstrated that individuals with Trisomy 21 (T21), the molecular cause of DS, exhibit constitutively active interferon (IFN) signaling driven by presence of four of the six IFN receptors (IFNRs), located in a single locus on chromosome 21 (chr21) (6). Follow-up studies have revealed 1) signs of IFN activation and chronic inflammation, including numerous cytokines related to CRS, in the plasma proteome of people with T21 (7, 8) and 2) widespread immune dysregulation and IFN hypersensitivity in the blood of people with DS (9, 10). As part of our ongoing work to understand the role of interferon dysregulation in Down syndrome (DS), we recently discovered that the Dp16 mouse model of DS is lethally hypersensitive to chronic innate immune stimulation with the TLR3 agonist polyinosinic: polycytidylic acid [P(I:C)]. Unpublished preliminary data in this proposal include: · P(I:C) treatment of Dp16 mice triggers release of cytokines, including several recently linked to poor prognosis in COVID-19, such as MCP-1, MIP-1α, and IP-10. · The lethal immune hypersensitivity in this model is associated with multi-organ inflammation and liver damage in particular. · The lethality, cytokine release, and inflammation induced by P(I:C) can all be blocked with the JAK1- specific inhibitor INCB054707. We hypothesize that JAK inhibitors are a therapeutically viable strategy to ameliorate COVID-19 associated cytokine release syndrome and associated morbidities. As such, our proposal is responsive to NOT-AI-20-031, particularly as a project “developing medical countermeasures and suitable animal models for pre-clinical testing of vaccines and therapeutics against SARS-CoV-2/COVID-19”. Furthermore, and in keeping with the spirit of the parent award, our data indicate that individuals with DS are likely to be a high-risk group that may experience more severe COVID-19 symptoms and associated cytokine storms in response to SARS-CoV- 2 infection. For this administrative supplement, our specific aim is: 1. To define the ability of all four FDA-approved JAK inhibitors to block lethality and associated cytokine storms in a mouse model of immune hypersensitivity. Encouraged by our preliminary results with the JAK1-specific inhibitor INCB054707, we propose here to test the ability of additional JAK inhibitors to rescue the hyperinflammatory phenotype in the Dp16 mouse model of Down syndrome. We will compare the four FDA-approved JAK inhibitors: baricitinib, ruxolitinib, tofacitinib, and upadacitinib, which have differing specificities for JAK1, JAK2, JAK3, and the related kinase TYK2, as well as varying pharmacodynamic and biodistribution properties. We will define the efficacy of each inhibitor and the therapeutic window in which inhibition of immune stimulation can be achieved. In addition, we will characterize hyperinflammation in key organs and tissues (e.g. lung, heart, liver) at the histological and molecular level to define how these organs respond to JAK inhibition. Importantly, our model system and study design allow for the assessment of inflammation in various tissues, many of which are linked to poor prognosis in individuals with COVID-19 (11-16). Completion of this aim will provide a considerable amount of pre-clinical data in support of ongoing clinical trials aimed at treating deleterious immune responses and serve to bolster the selection of agents available as COVID-19 therapeutics in the near term.

抽象的。 该申请根据NOT-AI-20-031提交给PA-18-591。 SARS-COV-2和COVID-19最近出现的迫切需要快速部署 应对当前大流行的治疗策略，并正在开发新疫苗的重大努力 然而，在短期内，预​​计这些努力的结果并不是抗病毒药。更多 即时方法是重新利用FDA批准的现有疗法以进行其他疾病以进行补救 与最严重的19个结果相关的症状，有可能挽救生命并减少生命 医疗保健系统负担。在此框架内，细胞因子释放综合征（CRS）也称为 急性呼吸遇险综合症，心力衰竭 19 Covid-19患者（1-5）的死亡。但是，尽管潜水员免疫支持策略 减弱细胞因子风暴正在临床试验中的COVID-19，临床前数据死亡 支持他们减弱细胞因子驱动的病理的用途。因此，我们在这里建议测试 janus激酶（JAKS）的FDA批准抑制剂可减轻猖ramp的细胞因子生产和多器官 无感染性致死性免疫超敏反应的小鼠模型中的炎症。 在过去的五年中，这种鼠标模型直接来自我们的工作，揭示了免疫的主要作用 唐氏综合症（DS）的失调。我们证明了三体分子（T21）的个体，分子 DS的原因，暴露于六个IFN中的四个驱动的持续活动性干扰（IFN）信号传导 受体（IFNR），位于21号染色体（CHR21）（6）的单个基因座中。后续研究表明1） 血浆中IFN激活和慢性感染的迹象，包括与CRS相关的许多细胞因子 具有T21（7，8）和2）的蛋白质组 DS患者的血液（9，10）。作为我们正在进行的工作的一部分，以了解干扰素失调的作用 唐氏综合症（DS），我们最近发现DS的DP16小鼠模型对 用TLR3激动剂聚光症：多环酸[P（i：C）]的慢性先天免疫刺激。未出版 此提案中的初步数据包括： P（i：c）DP16小鼠的治疗触发细胞因子的释放，其中几种与较差有关 Covid-19的预后，例如MCP-1，MIP-1α和IP-10。 ·该模型中的致命免疫异性与多器官注射和肝脏有关 特别是损坏。 ·P（I：C）诱导的致死性，细胞因子释放和炎症都可以通过JAK1-封闭。 特定抑制剂INCB054707。 我们假设JAK抑制剂是改善COVID-19的治疗策略 相关的细胞因子释放综合征和相关的病因。因此，我们的建议对 不是-ai-20-031，尤其是作为一个项目“开发医学对策和合适的动物模型 对SARS-COV-2/COVID-19”的疫苗和治疗的临床前测试。此外 有了父母奖的精神，我们的数据表明，患有DS的人可能是一个高风险群体 可能会遇到更严重的Covid-19症状和相关的细胞因子风暴，以应对SARS-COV- 2感染。对于这种行政补充，我们的具体目的是： 1。定义所有四个FDA批准的JAK抑制剂阻断致死性和相关细胞因子的能力 免疫超敏反应的小鼠模型中的暴风雨。 在JAK1特异性抑制剂INCB054707的初步结果的鼓励下，我们在这里提议测试 其他JAK抑制剂在DP16小鼠模型中挽救高炎性表型的能力 综合征。我们将比较四种FDA批准的JAK抑制剂：Bariticinib，ruxolitinib，tofacitinib和 upadacitinib，针对JAK1，JAK2，JAK3和相关激酶Tyk2的规格不同 不同的药效和生物分布特性。我们将定义每个抑制剂的效率和 可以实现抑制免疫刺激的治疗窗口。此外，我们将描述 在组织学和分子水平上的关键器官和组织（例如肺，心脏，肝脏）中的过度炎症 定义这些器官如何应对JAK抑制作用。 重要的是，我们的模型系统和研究设计允许在各种时间内评估炎症， 其中许多与COVID-19患者的预后不良有关（11-16）。这个目标的完成 提供一定数量的临床前数据，以支持旨在治疗的持续临床试验 有害免疫反应，并有助于加强作为Covid-19疗法可用的代理的选择 在短期内。