Inducible HMGB1 antagonist for viral-induced acute lung injury.

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.

Grant Number: 5R41HL167254-02
NIH Institute/Center: NIH
Principal Investigator: JORGE BLANCO