Severe and fatal influenza A virus (IAV) infections are associated with significant viral replication and damaging hyperinflammatory responses which can lead to morbidity, mortality and long-term multi-system organ damage. Therefore, new therapeutics that safely limit the severity of such respiratory viral infections are urgently needed.
LAT8881 is a synthetic form of a naturally occurring C-terminal fragment of growth hormone (GH). LAT8881 has an established clinical safety profile in humans and recently clinical proof-of-concept in neuropathic pain. Using a mouse model of severe IAV infection (104 PFU HKx31 H3N2) we defined a therapeutic efficacy profile for LAT8881. Daily intranasal delivery of LAT8881 from day 1 post-infection significantly improved survival outcomes correlated with reduced lung immunopathology. Increased disease resistance was associated with a dose-dependent reduction in lung viral loads and airway levels of inflammatory cytokines, while increasing levels of protective alveolar macrophages.
LAT8881 is a 16 amino acid cyclic peptide, however, short linear peptides are typically easier to manufacture and formulate for delivery. Daily treatment with a linear, 6 amino acid derivate of LAT8881 (LAT9997) also significantly limited IAV disease severity and improved survival outcomes, in a manner similar to that of LAT8881 treatment. Additionally, LAT9997 reduced presence of damage markers, vascular leak, epithelial cell death and neutrophil infiltration in the airways. Using fluorescently labelled versions of LAT9997 we have demonstrated uptake of the peptide is largely by epithelial cells in both naïve and IAV-infected mouse lungs. To uncover the cellular pathways involved we conducted a broad proteomic screen on lung lavage and serum samples taken from mice infected with IAV and treated with LAT9997 or vehicle control. Ongoing studies aim to validate the host protective pathway in vivo and in vitro using human cells. Together our data suggests potential for rapid deployment of GH-derived peptides as treatment for influenza infection.