DAS181, A SIALIDASE FUSION PROTEIN, PROTECTS HUMAN AIRWAY EPITHELIUM AGAINST INFLUENZA VIRUS INFECTION: AN IN VITRO PHARMACODYNAMIC ANALYSIS.
This study by researchers at NexBio and the University of Hong Kong demonstrated that MatTek’s EpiAirway in vitro 3-D human tracheal/bronchial tissue equivalent can be used to model the pharmacodynamics of a new drug formulation that inhibits influenza virus infection. Objectives: The influenza virus (IFV) infection models commonly used to evaluate antiviral agents (e.g. MDCK cell line and mice) are limited by physiological differences from the human respiratory tract in vivo. Here researchers report the pharmacodynamics of DAS181, a sialidase fusion protein that inhibits influenza infection, in the model systems of well-defined human airway epithelium (EpiAirway) culture and ex vivo culture of fresh human bronchial tissue, both of which are close mimics of the human respiratory tract in vivo. Methods: EpiAirway cultures and ex vivo human bronchi were used to evaluate the sialic acid removal and regeneration efficiency and influenza virus inhibition after various DAS181 treatment levels and regimens. Results: DAS181 effectively desialylates EpiAirway cultures and ex vivo bronchi tissues and therefore potently inhibits replication of different influenza virus strains. The treatment effect of DAS181 occurs immediately upon application to the epithelial surface and is unaffected by the respiratory mucus. In both EpiAirway and human bronchial tissue, the inhibitory effect of DAS181 treatment lasts for at least 2 days. Approximately 80% epithelial surface desialylation and significant anti-IFV efficacy can be achieved at topical concentrations of DAS181 in the range of 5–10 µg/cm2 when applied once daily. An additional treatment or a higher loading dose of DAS181 on the first day provides significant additional treatment benefit. Comparing the effect of DAS181 versus its two analogues, DAS180 and DAS185, has confirmed that sialidase function is critical for DAS181, and the cell-binding domain (amphiregulin tag) prolongs DAS181 retention and potentiates its function. Conclusions: These results provide valuable insights into DAS181 treatment dose and potential regimens in the clinical setting.
AIR-100, AIR196-HTS, Antiviral activity, Antiviral drug treatment, Apical washes, Apoptosis array, Enzyme-linked lectin assay, EpiAirway, Infection, Influenza virus, Mucociliary clearance, Pharmacodynamic analysis, Prophylaxis studies, Resialylation , Sialic acid, Sialic acid turnover, Sialidase fusion protein
DAS181, Sialidase fusion protein
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