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Principal Investigator: JORGE C BLANCO
Organization: SIGMOVIR BIOSYSTEMS, INC.
Fiscal Year: 2024
Award: $488,080
Funding agency: National Heart Lung and Blood Institute
For more than a decade, our work has focused on development of therapeutic interventions for viral- and
bacterial-induced acute lung injury (ALI) and the more severe acute respiratory distress syndrome (ARDS).
Significantly, we identified the Toll-like receptor 4 (TLR4) signaling pathway as key to the host response to
influenza and secondary bacterial infection following influenza. We also identified High Mobility Group Box 1
(HMGB1), a host-derived “danger-associated molecular pattern” (DAMP), as a biomarker of disease severity for
multiple respiratory viruses and detected greatly elevated levels in sera from patients hospitalized for severe
influenza and SARS-CoV-2 infections. Importantly, our data indicate that HMGB1 is a central mediator of
influenza-induced respiratory disease that acts by stimulating TLR4/MD-2 to elicit the potent inflammatory
response associated with ALI/ARDS. Therapeutic administration of TLR4 antagonists (e.g., Eritoran and many
others), as well as small molecule HMGB1 antagonists, mitigate the life-threatening pulmonary manifestations
of acute lung injury (ALI) and lethality in preclinical rodent models. The identification of these promising
therapeutic targets has led us to the central hypothesis that our findings may well be applicable to other ALI-
inducing agents. Indeed, since our earliest reports of the efficacy of the TLR4 antagonist, Eritoran, in influenza-
induced disease in both mice and cotton rats (Sigmodon hispidus, a species uniquely susceptible to non-adapted
human viruses), this agent has been reported to blunt disease in animal models of Ebola virus and Dengue virus,
leading to a reduction in cytokine and chemokine production and reduced disease symptoms. Given the clinical
relevance of ALI and ARDS that has been exposed by the SARS-CoV-2 pandemic, and the striking similarities
between influenza- and SARS-Cov-2-induced ALI/ARDS caused by a cytokine storm leading to loss of
homeostasis and, ultimately, multiorgan failure and death, we propose, as the central goal of this phase I STTR,
to evaluate the therapeutic efficacy of our newly developed, inflammation-inducible, adenoviral vector encoding
the HMGB1 antagonist, “HMGB1 Box A,” to ameliorate severe influenza-induced inflammation. We will test the
efficacy of our intervention in murine models of LPS-induced lung inflammation and mouse-adapted influenza
infection, and in cotton rats challenged with non-adapted human influenza strains for which we have correlated
HMGB1 levels with disease severity. We predict that our innovative strategy will provide a novel approach to
treatment of inflammatory lung disease that is mediated by multiple non-infectious and infectious agents that
cause ALI/ARDS.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ARDS><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Ad vector><Address><Adenoviral Vector><Adenoviridae><Adenovirus Vector><Adenoviruses><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Agonist><Airway infections><Amphoterin><Amphoterin Gene><Animal Model><Animal Models and Related Studies><Autoregulation><Bacterial Infections><Biological Markers><Body Tissues><Breakbone Fever Virus><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 associated cytokine storm><COVID-19 crisis><COVID-19 cytokine storm><COVID-19 epidemic><COVID-19 era><COVID-19 exposure><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 induced cytokine storm><COVID-19 infection><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 related cytokine storm><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 infection><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular injury><Cessation of life><Chemotactic Cytokines><Chromosomal Protein, Nonhistone, HMG1><Chromosomal Protein, Nonhistone, HMG1 Gene><CoV-2><CoV2><Cotton Rats><DENV><Da Nang Lung><Data><Death><Dengue Virus><Dengue fever virus><Development><Dimerization><Disease><Disease Progression><Disorder><EBOV><Ebola virus><Ebola-like Viruses><Engineering><Experimental Animal Model><FM1 Gene Product><Family><Gene Expression><Goals><Grippe><HMG-1><HMG-1 Gene><HMG-1 Protein><HMG1><HMG1 Gene><HMG3><HMG3 Gene><HMGB1><HMGB1 Protein><HMGB1 gene><Heparin-Binding Protein p30><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1><High-Mobility Group Box 1 Gene><Homeostasis><Homolog of Drosophila TOLL><Homologous Chemotactic Cytokines><Hospital Admission><Hospitalization><Human><Immune response><Immunological response><Infectious Agent><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Influenza><Injury><Innate Immune Response><Intercrines><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Life><Ligands><Lipopolysaccharides><Lung><Lung Inflammation><Lung Respiratory System><MOF syndrome><Mediating><Mediator><Mice><Mice Mammals><Modern Man><Molecular><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Nonhistone Chromosomal Protein HGM1><Nonhistone Chromosomal Protein HGM1 Gene><Pathway interactions><Patients><Pattern><Pattern recognition receptor><Phase><Physiological Homeostasis><Pneumonitis><Predisposition><Process><Production><Protein Dimerization><Publishing><Pulmonary Inflammation><Receptor Protein><Reporting><Research><Resolution><Respiratory Disease><Respiratory Infections><Respiratory System 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Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 exposure><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Shock Lung><Sigmodon><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Small Business Technology Transfer Research><Sterility><Stiff lung><Structure><Sulfoglucuronyl Carbohydrate Binding Protein><Sulfoglucuronyl Carbohydrate Binding Protein Gene><Susceptibility><Symptoms><System><TLR protein><TLR4><TLR4 gene><Testing><Therapeutic><Therapeutic 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