Phase I Amount
$1,026,596
Acute respiratory distress syndrome (ARDS) is a severe life-threatening complication that can be caused byviral infection. The disease is characterized by cytokine-driven hyperinflammation and leukocytes countchanges. 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 ininfluenza and coronavirus infections. Therefore, therapeutic strategies targeting hyperactivated neutrophilsmay be useful for mitigating ARDS.The gut microbiota has emerged as an important regulator of the host immunity. Microbial components fromthe gut microbiota can regulate neutrophil functions, modulating the magnitude of inflammatory responses notonly locally, but also systemically. The gut-lung microbiome connection implicates the gut microbiome as arelevant 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 quicklyand 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 novelstrategy that is neither limited by our understanding of the viral pathogens` biology nor by antigenicity ormutational 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 naturalmicrobiome-associated immunological processes with the potential to diminish lung neutrophilia, reduceinflammation, upregulate regulatory T cells, and restore airways epithelial barrier to balance and reset patient'simmunological repertoire. R-3750 is inexpensive to manufacture, is orally dosed, and is stored stably at roomtemperature. R-3750, Lactococcus (L.) lactis engineered to express Surface Layer Protein A (SlpA), works viaoral targeted delivery of SlpA to the intestinal tract where it engages mucosal dendritic cells lining the intestinaltract to reset immunological repertoires to blunt inflammatory processes. R-3750 induces exquisite differentialgene 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 iscommonly 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 mechanismof action in several models of lung injuries, while completing key IND-enabling activities. R-3750 represents anew revolutionary therapy that combines the safety, economics, and ease of administration of a probiotic withthe targeted delivery of an immunologically relevant protein that can quickly be deployed to save lives of virallyinfected patients with a hyperactive immune response.
Public Health Relevance Statement: PROJECT NARRATIVE
The dysregulated immune response in ARDS patients is directly related to severity and lethality of endemic
and pandemic respiratory viruses. R-3750 is a functionally directed synthetic biology medicine that rebalances
the immune system, eliminating self-destructive immune responses without compromising the immunological
recognition of pathogens. R-3750 combines the safety and ease of administration of a probiotic with the
targeted delivery of an immunologically focused drug that can be used to mitigate viral-induced ARDS.
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