SBIR-STTR Award

Direct to Phase II

This application is to support a clinical trial of the first mRNA engineered cell therapy for Acute Respiratory Distress Syndrome (ARDS), including ARDS caused by COVID-19. The FDA has already reviewed the IND application and determined that the study may proceed. ARDS is a severe inflammatory respiratory failure that kills an estimated 80,000 Americans each year. 80% of ARDS patients require mechanical ventilation. No FDA-approved therapies for ARDS are available. ARDS may result from infectious or non-infectious (e.g., traumatic or chemical) insults. COVID-19 is currently the most common cause of ARDS, and the vast majority of COVID-19 deaths are due to ARDS. Neutrophil Extracellular Traps (NETs) drive the hyperactive inflammatory response in ARDS and COVID-19, and presence of NETs correlates strongly with ARDS severity. NETs are produced by locally-trafficked neutrophils undergoing NETosis, a programmed cell death where the cells lyse to secrete DNA decorated with inflammatory proteins. Low amounts of NETs are thought to help entrap infection, but hyperactivated neutrophils produce large quantities of NETs that cause hypoxia and immune thrombi due to physical blockade of alveoli and microvasculature. A NET-degrading therapy therefore would be a significant advance in treatment of ARDS. Descartes-30 is the first allogeneic (i.e., off-the-shelf) engineered human Mesenchymal Stem Cell (MSC) therapy secreting a combination of two potent NET-degrading enzymes. In this Phase 1/2a study, the hypothesis to be tested is that Descartes-30 will be well tolerated and show evidence of efficacy in patients with moderate to severe ARDS and COVID- 19. Aims are to determine the maximum tolerated dose and evidence of preliminary efficacy, define pharmacokinetic properties and biologic correlates of disease, and establish a validated Potency assay for use in later-stage clinical development. These data will inform the design of a controlled registration study in patients with moderate-to-severe ARDS. Public Health Relevance Statement NARRATIVE Acute Respiratory Distress Syndrome (ARDS), including ARDS due to COVID-19, is a severe inflammatory respiratory failure that kills an estimated 80,000 Americans each year; 80% of ARDS patients require mechanical ventilation and no FDA-approved therapies for ARDS are available. ARDS and COVID-19 are thought to be caused or exacerbated by sticky webs of DNA and inflammatory proteins called Neutrophil Extracellular Traps (NETs). Work in this SBIR supports clinical development of Descartes-30, the first clinical-stage therapy specifically designed to eliminate NETs and the first engineered cell therapy specifically targeting ARDS and COVID-19.

Project Terms:
Vasoactive Agonists ; Vasoconstrictor Drugs ; Vasoconstrictors ; Vasopressor Agents ; vasopressor ; Work ; cytokine ; Immunophenotyping ; Immunologic Subtyping ; immunophenotype ; Measures ; Thrombus ; Apoptosis ; Apoptosis Pathway ; Programmed Cell Death ; Bronchoalveolar Lavage ; Bronchioalveolar Lavage ; Bronchopulmonary Lavage ; Lung Lavage ; bronchopulmonary lavage therapy ; Mechanical ventilation ; mechanical respiratory assist ; mechanically ventilated ; Clinical ; Phase ; Biological ; Chemicals ; Hypoxia ; Hypoxic ; Oxygen Deficiency ; Acute Lung Injury ; Acute Pulmonary Injury ; Inflammation Mediators ; inflammatory mediator ; Internet ; WWW ; web ; world wide web ; Letters ; cell mediated therapies ; cell-based therapeutic ; cell-based therapy ; cellular therapy ; Cell Therapy ; Inflammatory ; exhaustion ; Hour ; Immunes ; Immune ; Severities ; extracellular ; Infusion ; Infusion procedures ; American ; contagion ; trafficking ; Toxicities ; Toxic effect ; Position ; Positioning Attribute ; Maximal Tolerated Dose ; Maximally Tolerated Dose ; Maximum Tolerated Dose ; Modeling ; Sampling ; Property ; stem cell based therapy ; stem cell mediated therapy ; stem cell therapeutics ; stem cell treatment ; stem cell-based treatment ; stem cell therapy ; lung failure ; pulmonary failure ; Respiratory Failure ; Inflammatory Response ; Mesenchymal Progenitor Cell ; Mesenchymal progenitor ; Mesenchymal Stem Cells ; Dose ; Data ; Dose-Limiting ; Allogenic ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Advanced Development ; design ; designing ; FDA approved ; clinical lot ; operation ; Therapy trial ; cell free DNA ; cell free circulating DNA ; clinical development ; single-cell RNA sequencing ; scRNA-seq ; single cell RNA-seq ; single cell RNAseq ; secondary endpoint ; secondary end point ; primary endpoint ; primary end point ; pharmacokinetics and pharmacodynamics ; PK/PD ; COVID-19 ; COVID19 ; CV-19 ; CV19 ; corona virus disease 2019 ; coronavirus disease 2019 ; COVID-19 mortality ; COVID-19 associated death ; COVID-19 associated fatality ; COVID-19 associated mortality ; COVID-19 death ; COVID-19 fatality ; COVID-19 induced death ; COVID-19 induced fatality ; COVID-19 induced mortality ; COVID-19 related death ; COVID-19 related fatality ; COVID-19 related mortality ; COVID19 associated death ; COVID19 associated fatality ; COVID19 associated mortality ; COVID19 death ; COVID19 fatality ; COVID19 induced death ; COVID19 induced fatality ; COVID19 induced mortality ; COVID19 mortality ; COVID19 related death ; COVID19 related fatality ; COVID19 related mortality ; SARS-CoV-2 associated death ; SARS-CoV-2 associated fatality ; SARS-CoV-2 associated mortality ; SARS-CoV-2 death ; SARS-CoV-2 fatality ; SARS-CoV-2 induced death ; SARS-CoV-2 induced fatality ; SARS-CoV-2 induced mortality ; SARS-CoV-2 mortality ; SARS-CoV-2 related death ; SARS-CoV-2 related fatality ; SARS-CoV-2 related mortality ; coronavirus disease 2019 associated death ; coronavirus disease 2019 associated fatality ; coronavirus disease 2019 associated mortality ; coronavirus disease 2019 death ; coronavirus disease 2019 fatality ; coronavirus disease 2019 induced death ; coronavirus disease 2019 induced fatality ; coronavirus disease 2019 induced mortality ; coronavirus disease 2019 mortality ; coronavirus disease 2019 related death ; coronavirus disease 2019 related fatality ; coronavirus disease 2019 related mortality ; death due to COVID-19 ; death due to COVID19 ; death due to SARS-CoV-2 ; death due to coronavirus disease 2019 ; death due to severe acute respiratory syndrome coronavirus 2 ; death in COVID ; death in COVID-19 ; death in SARS-CoV-2 ; death in coronavirus disease ; death in coronavirus disease 2019 ; death in severe acute respiratory syndrome coronavirus 2 ; fatality due to COVID-19 ; fatality due to COVID19 ; fatality due to SARS-CoV-2 ; fatality due to coronavirus disease 2019 ; fatality due to severe acute respiratory syndrome coronavirus 2 ; mortality due to COVID-19 ; mortality due to COVID19 ; mortality due to SARS-CoV-2 ; mortality due to coronavirus disease 2019 ; mortality due to severe acute respiratory syndrome coronavirus 2 ; severe acute respiratory syndrome coronavirus 2 associated death ; severe acute respiratory syndrome coronavirus 2 associated fatality ; severe acute respiratory syndrome coronavirus 2 associated mortality ; severe acute respiratory syndrome coronavirus 2 death ; severe acute respiratory syndrome coronavirus 2 fatality ; severe acute respiratory syndrome coronavirus 2 induced death ; severe acute respiratory syndrome coronavirus 2 induced fatality ; severe acute respiratory syndrome coronavirus 2 induced mortality ; severe acute respiratory syndrome coronavirus 2 mortality ; severe acute respiratory syndrome coronavirus 2 related death ; severe acute respiratory syndrome coronavirus 2 related fatality ; severe acute respiratory syndrome coronavirus 2 related mortality ; COVID-19 patient ; COVID infected patient ; COVID patient ; COVID positive patient ; COVID-19 infected patient ; COVID-19 positive patient ; COVID19 patient ; COVID19 positive patient ; SARS-CoV-2 infected patient ; SARS-CoV-2 patient ; SARS-CoV-2 positive patient ; coronavirus disease 2019 infected patient ; coronavirus disease 2019 patient ; coronavirus disease 2019 positive patient ; coronavirus disease infected patient ; coronavirus disease patient ; coronavirus disease positive patient ; coronavirus patient ; patient infected with COVID ; patient infected with COVID-19 ; patient infected with SARS-CoV-2 ; patient infected with coronavirus disease ; patient infected with coronavirus disease 2019 ; patient infected with severe acute respiratory syndrome coronavirus 2 ; patient with COVID ; patient with COVID-19 ; patient with COVID19 ; patient with SARS-CoV-2 ; patient with coronavirus disease ; patient with coronavirus disease 2019 ; patient with severe acute respiratory distress syndrome coronavirus 2 ; severe acute respiratory syndrome coronavirus 2 infected patient ; severe acute respiratory syndrome coronavirus 2 patient ; severe acute respiratory syndrome coronavirus 2 positive patient ; Hyperactivity ; Anti-Inflammatory Agents ; Anti-Inflammatories ; Anti-inflammatory ; Antiinflammatories ; Antiinflammatory Agents ; antiinflammatory ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Blood ; Blood Reticuloendothelial System ; Cell Death ; necrocytosis ; Cells ; Cell Body ; Clinical Research ; Clinical Study ; Clinical Trials ; Deoxyribonucleases ; DNA Nucleases ; DNase ; Disease ; Disorder ; DNA ; Deoxyribonucleic Acid ; intravenous administration ; Eligibility Determination ; Eligibility ; Protocol Screening ; Engineering ; Enzymes ; Enzyme Gene ; Fluorometry ; Gene Expression ; Cyclic GMP ; Guanosine Cyclic Monophosphate ; cGMP ; Histone H3 ; Human Engineering ; Infection ; Kidney ; Kidney Urinary System ; renal ; Length of Stay ; Number of Days in Hospital ; hospital days ; hospital length of stay ; hospital stay ; Lung ; Lung Respiratory System ; pulmonary ; macrophage ; Mφ ; Maps ; mortality ; Mus ; Mice ; Mice Mammals ; Murine ; neutrophil ; Blood Neutrophil ; Blood Polymorphonuclear Neutrophil ; Marrow Neutrophil ; Neutrophilic Granulocyte ; Neutrophilic Leukocyte ; Polymorphonuclear Cell ; Polymorphonuclear Leukocytes ; Polymorphonuclear Neutrophils ; Patients ; Peroxidases ; Hemi-Myeloperoxidase ; Myeloperoxidase ; Drug Kinetics ; Pharmacokinetics ; Production ; Proteins ; research and development ; Development and Research ; R & D ; R&D ; Adult Respiratory Distress Syndrome ; ARDS ; Acute Respiratory Distress ; Acute Respiratory Distress Syndrome ; Adult ARDS ; Adult RDS ; Da Nang Lung ; Shock Lung ; Stiff lung ; wet lung ; Risk ; RNA ; Non-Polyadenylated RNA ; RNA Gene Products ; Ribonucleic Acid ; Messenger RNA ; mRNA ; Safety ; Specificity ; Testing ; Time ; Vasoconstrictor Agents ;