A Novel Synthetic Biology-Derived Microbiome Therapeutic to Treat Viral-Induced Acute Respiratory Distress Syndrome (ARDS)

项目总结 急性呼吸窘迫综合征(ARDS)是一种严重威胁生命的并发症，可由以下原因引起 病毒感染。这种疾病的特点是细胞因子驱动的高度炎症和白细胞计数 改变。先天免疫反应与ARDS的免疫发病机制有关。在这方面， 中性粒细胞在ARDS的发展过程中被强调为重要的效应细胞，如 流感和冠状病毒感染。因此，针对高度激活的中性粒细胞的治疗策略 可能对减轻ARDS有用。 肠道微生物区系已成为宿主免疫的重要调节因子。微生物组分来自 肠道微生物区系可以调节中性粒细胞的功能，调节炎症反应的幅度，而不是 不仅是局部的，而且是系统的。肠道-肺微生物组连接意味着肠道微生物组是一种 降低病毒介导的急性呼吸窘迫综合征病情的相关新策略。 当前的流行病告诉我们，我们需要能够迅速部署的新的、革命性的疗法 而且对世界各地的普通民众来说也很容易。在病毒诱导的ARDS的背景下，以中性粒细胞为靶点， 恢复呼吸道上皮细胞屏障，并重新聚焦免疫反应是一个关键和新颖的 这一策略既不受我们对病毒病原体生物学的了解，也不受抗原性或 突变状态，但可以通过利用现有的宿主免疫谱系发挥广泛的作用。 Rise Treeutics正在开发R-3750，这是一种功能定向的合成益生菌，与天然 微生物组相关免疫过程有可能减少肺中性粒细胞增多，减少 炎症，上调调节性T细胞，恢复呼吸道上皮屏障，以平衡和重置患者的 免疫学曲目。R-3750制造成本低，口服给药，并在室温下稳定储存 温度。R-3750，乳球菌(L.)经改造可表达表层蛋白A(SLpA)的乳酸通过 口服靶向递送SLpA到肠道，在那里它与肠道内的粘膜树突状细胞接触 重置免疫系统以钝化炎症过程。R-3750带来精致的差异化 基因表达导致抗病毒防御机制上调和PRO-2下调 炎症途径。在动物模型中还没有发现R-3750的安全问题，乳酸乳杆菌 通常在我们的饮食中摄入，因为这种菌株被用作益生菌和在食品工业中使用。 这项第二阶段的提案寻求资金，以确定新的生物标志物，并进一步了解R-3750的机制 在几种肺损伤模型中发挥作用，同时完成关键的促进IND的活动。R-3750代表一种 一种新的革命性疗法，将益生菌的安全性、经济性和易用性与 一种免疫相关蛋白的靶向传递，可以迅速部署以挽救病毒感染者的生命 免疫反应过度活跃的感染者。

PROJECT SUMMARY Acute respiratory distress syndrome (ARDS) is a severe life-threatening complication that can be caused by viral infection. The disease is characterized by cytokine-driven hyperinflammation and leukocytes count changes. The innate immune response has been linked to ARDS immunopathogenesis. In this regard, neutrophils have been highlighted as essential effector cells in the development of ARDS, as demonstrated in influenza and coronavirus infections. Therefore, therapeutic strategies targeting hyperactivated neutrophils may be useful for mitigating ARDS. The gut microbiota has emerged as an important regulator of the host immunity. Microbial components from the gut microbiota can regulate neutrophil functions, modulating the magnitude of inflammatory responses not only locally, but also systemically. The gut-lung microbiome connection implicates the gut microbiome as a relevant new strategy to lessen disease severity in viral-mediated ARDS. The current pandemic has taught us that we need novel, revolutionary therapies that can be deployed quickly and easily to the general population worldwide. In the context of viral-induced ARDS, targeting neutrophils, restoring airways epithelial cell barrier, and refocusing the immune response represents a critical and novel strategy that is neither limited by our understanding of the viral pathogens` biology nor by antigenicity or mutational status but can act broadly by leveraging the existing host immune repertoire. Rise Therapeutics is developing R-3750, a functionally directed synthetic probiotic that engages natural microbiome-associated immunological processes with the potential to diminish lung neutrophilia, reduce inflammation, upregulate regulatory T cells, and restore airways epithelial barrier to balance and reset patient’s immunological repertoire. R-3750 is inexpensive to manufacture, is orally dosed, and is stored stably at room temperature. R-3750, Lactococcus (L.) lactis engineered to express Surface Layer Protein A (SlpA), works via oral targeted delivery of SlpA to the intestinal tract where it engages mucosal dendritic cells lining the intestinal tract to reset immunological repertoires to blunt inflammatory processes. R-3750 induces exquisite differential gene expression leading to upregulation of anti-viral defense mechanisms and down-regulation of pro- inflammatory pathways. No safety issues for R-3750 have ever been noticed in animal models, and L. lactis is commonly ingested in our diet, as this strain is used as a probiotic and in the food industry. This Phase II proposal seeks funding to identify novel biomarkers and further understand R-3750 mechanism of action in several models of lung injuries, while completing key IND-enabling activities. R-3750 represents a new revolutionary therapy that combines the safety, economics, and ease of administration of a probiotic with the targeted delivery of an immunologically relevant protein that can quickly be deployed to save lives of virally infected patients with a hyperactive immune response.