Document text
Principal Investigator: Gary Fanger
Organization: RISE THERAPEUTICS, LLC
Fiscal Year: 2024
Award: $984,405
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Food Industry><Funding><Future><GI microbiome><GI microbiota><Gastrointestinal microbiota><General Population><General Public><Genes><Grant><Grippe><Health><Hematology><Histopathology><Human><Hyperactivity><Immune><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunomodulation><Inflammation><Inflammatory><Inflammatory Response><Influenza><Infrastructure><Ingestion><Innate Immune Response><Intestinal><Intestines><Investments><Lactococcus lactis><Leukocyte Count><Leukocyte Number><Leukocytes><Leukocytes Reticuloendothelial System><Life><Link><Lung><Lung Respiratory System><Lung damage><Marrow Neutrophil><Marrow leukocyte><Measures><Mediating><Medication><Medicine><Mice><Mice Mammals><Modeling><Modern Man><Mucosa><Mucosal Tissue><Mucous Membrane><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Neutrophil 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Expression><Tissues><Toxicology><Treg><Up-Regulation><Upregulation><Veiled Cells><Viral><Viral Diseases><Virus Diseases><White Blood Cell Count><White Blood Cell Count procedure><White Blood Cells><White Cell><Work><airway epithelium><balance><balance function><bio-markers><biologic marker><biomarker><biomarker identification><bowel><capsule><clinical test><combination therapy><combined modality treatment><combined treatment><cultured cell line><current pandemic><cytokine><developmental><diets><digestive tract microbiome><disease severity><drug development><drug/agent><economic><enteric microbial community><enteric microbiome><enteric microbiota><enzyme linked immunoassay><flow cytophotometry><flu infection><flu virus infection><gastrointestinal microbial flora><gastrointestinal microbiome><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiome><gut microbiota><gut microbiotic><gut 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model><mutation status><mutational status><neutrophil><new approaches><new drug treatments><new drugs><new marker><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel biomarker><novel drug treatments><novel drugs><novel marker><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><pandemic><pandemic disease><pathogen><pathogenic virus><pathway><pharmaceutical><present pandemic><programs><psychological defense mechanism><pulmonary><pulmonary damage><pulmonary injury><pulmonary microbiome><pulmonary tissue damage><pulmonary tissue injury><regulatory T-cells><research clinical testing><respiratory tract epithelium><respiratory virus><screening><screenings><site targeted delivery><social role><synthetic biology><targeted delivery><thymus derived lymphocyte><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease><wet lung><white blood cell><white blood corpuscle>