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

项目摘要 急性呼吸窘迫综合征（ARDS）是一种严重的危及生命的并发症， 病毒感染这种疾病的特征是由尼古丁驱动的炎症和白细胞计数 变化先天性免疫应答与ARDS免疫发病机制有关。在这方面，委员会注意到， 嗜中性粒细胞在ARDS的发展中作为重要的效应细胞已经被强调，如 流感和冠状病毒感染。因此，针对过度活化的中性粒细胞的治疗策略 可能有助于缓解ARDS。 肠道微生物群已成为宿主免疫的重要调节因子。微生物成分来自 肠道微生物群可以调节中性粒细胞功能，调节炎症反应的程度， 不仅是局部的，而且是系统的。肠-肺微生物组的联系暗示肠道微生物组是一种 相关的新策略，以减轻病毒介导的ARDS的疾病严重程度。 当前的大流行告诉我们，我们需要能够迅速部署的新颖的、革命性的疗法 并且很容易传播到全世界的普通人群。在病毒诱导的ARDS的背景下，靶向中性粒细胞， 恢复气道上皮细胞屏障，并重新聚焦免疫反应代表了一个关键的和新的 这种策略既不受我们对病毒病原体生物学的理解的限制，也不受抗原性的限制， 突变状态，但可以通过利用现有的宿主免疫库广泛发挥作用。 Rise Therapeutics正在开发R-3750，这是一种功能性合成益生菌， 微生物组相关的免疫过程，有可能减少肺部嗜酸性粒细胞， 炎症，上调调节性T细胞，恢复气道上皮屏障以平衡和重置患者的 免疫系统R-3750生产成本低，口服给药，并在室温下稳定储存。 温度R-3750，乳球菌属（Lactococcus（L.）乳酸菌工程表达表面层蛋白A（SlpA），通过 将SlpA经口靶向递送至肠道，在肠道中它与肠粘膜内衬的树突细胞接合， 重新设置免疫系统以减弱炎症过程。R-3750诱导精密微分 基因表达导致抗病毒防御机制的上调和前- 炎症通路。在动物模型中没有发现R-3750的安全性问题，L。乳酸是 通常在我们的饮食中摄入，因为这种菌株被用作益生菌和食品工业。 该第二阶段提案寻求资金，以确定新的生物标志物，并进一步了解R-3750的机制 在完成关键的IND使能活动的同时，R-3750代表 一种新的革命性疗法，将益生菌的安全性、经济性和易于服用性与 靶向递送免疫相关蛋白，可以快速部署以挽救病毒感染者的生命， 免疫反应过度的感染患者

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.