PT  - JOURNAL ARTICLE
AU  - Longlong Si
AU  - Haiqing Bai
AU  - Melissa Rodas
AU  - Wuji Cao
AU  - Crystal Yuri Oh
AU  - Amanda Jiang
AU  - Rasmus Moller
AU  - Daisy Hoagland
AU  - Kohei Oishi
AU  - Shu Horiuchi
AU  - Skyler Uhl
AU  - Daniel Blanco-Melo
AU  - Randy A. Albrecht
AU  - Wen-Chun Liu
AU  - Tristan Jordan
AU  - Benjamin E. Nilsson-Payant
AU  - James Logue
AU  - Robert Haupt
AU  - Marisa McGrath
AU  - Stuart Weston
AU  - Atiq Nurani
AU  - Seong Min Kim
AU  - Danni Y. Zhu
AU  - Kambez H. Benam
AU  - Girija Goyal
AU  - Sarah E. Gilpin
AU  - Rachelle Prantil-Baun
AU  - Rani K. Powers
AU  - Kenneth Carlson
AU  - Matthew Frieman
AU  - Benjamin R. tenOever
AU  - Donald E. Ingber
TI  - Human organ chip-enabled pipeline to rapidly repurpose therapeutics during viral pandemics
AID  - 10.1101/2020.04.13.039917
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.13.039917
4099  - http://biorxiv.org/content/early/2020/08/19/2020.04.13.039917.short
4100  - http://biorxiv.org/content/early/2020/08/19/2020.04.13.039917.full
AB  - The rising threat of pandemic viruses, such as SARS-CoV-2, requires development of new preclinical discovery platforms that can more rapidly identify therapeutics that are active in vitro and also translate in vivo. Here we show that human organ-on-a-chip (Organ Chip) microfluidic culture devices lined by highly differentiated human primary lung airway epithelium and endothelium can be used to model virus entry, replication, strain-dependent virulence, host cytokine production, and recruitment of circulating immune cells in response to infection by respiratory viruses with great pandemic potential. We provide a first demonstration of drug repurposing by using oseltamivir in influenza A virus-infected organ chip cultures and show that co-administration of the approved anticoagulant drug, nafamostat, can double oseltamivir’s therapeutic time window. With the emergence of the COVID-19 pandemic, the Airway Chips were used to assess the inhibitory activities of approved drugs that showed inhibition in traditional cell culture assays only to find that most failed when tested in the Organ Chip platform. When administered in human Airway Chips under flow at a clinically relevant dose, one drug – amodiaquine - significantly inhibited infection by a pseudotyped SARS-CoV-2 virus. Proof of concept was provided by showing that amodiaquine and its active metabolite (desethylamodiaquine) also significantly reduce viral load in both direct infection and animal-to-animal transmission models of native SARS-CoV-2 infection in hamsters. These data highlight the value of Organ Chip technology as a more stringent and physiologically relevant platform for drug repurposing, and suggest that amodiaquine should be considered for future clinical testing.Competing Interest StatementD.E.I. is a founder and holds equity in Emulate Inc., and chairs its advisory board. D.E.I., L. S., R. P., K. H. B., H. B., and M. R. are inventors on relevant patent applications submitted by Harvard University.