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

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.