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Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics

Longlong Si, Haiqing Bai, Melissa Rodas, Wuji Cao, Crystal Yuri Oh, Amanda Jiang, Atiq Nurani, Danni Y. Zhu, Girija Goyal, Sarah E. Gilpin, Rachelle Prantil-Baun, Donald E. Ingber
doi: https://doi.org/10.1101/2020.04.13.039917
Longlong Si
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Haiqing Bai
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Melissa Rodas
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Wuji Cao
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Crystal Yuri Oh
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Amanda Jiang
3Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115
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Atiq Nurani
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Danni Y. Zhu
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Girija Goyal
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Sarah E. Gilpin
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Rachelle Prantil-Baun
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
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Donald E. Ingber
1Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115
2Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, MA 02139
3Vascular Biology Program and Department of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115
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  • For correspondence: don.ingber@wyss.harvard.edu
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Abstract

Rapidly spreading viral pandemics, such as those caused by influenza and SAR-CoV-2 (COVID19), require rapid action and the fastest way to combat this challenge is by repurposing existing drugs as anti-viral therapeutics. Here we first show that human organ-on-a-chip (Organ Chip) microfluidic culture devices lined by a highly differentiated, primary, human lung airway epithelium cultured under an air-liquid interface and fed by continuous medium flow 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 influenza, as well as effects of existing and novel therapeutics. These Airway Chips, which contain human lung epithelial cells that express high levels of ACE2 and TMPRSS2, were then used to assess the inhibitory activities of 7 clinically approved drugs (chloroquine, arbidol, toremifene, clomiphene, amodiaquine, verapamil, and amiodarone) that we found inhibit infection by viral pseudoparticles expressing SARS-CoV-2 spike protein in human Huh-7 cells, and others recently showed suppress infection by native SARS-CoV-2 in Vero cells. However, when these drugs were administered under flow at the maximal concentration in blood reported in clinical studies in human Airway Chips, only two of these drugs — amodiaquine and toremifene — significantly inhibited entry of the pseudotyped SARS-CoV-2 virus. This work suggests that human Organ Chip technology may be used in conjunction with existing rapid cell-based screening assays to study human disease pathogenesis and expedite drug repurposing in biothreat crises caused by pandemic viruses.

Competing Interest Statement

D.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.

Footnotes

  • The Competing Interest Statement -The authors have declared no competing interest- has been revised to -D.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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 15, 2020.
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Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics
Longlong Si, Haiqing Bai, Melissa Rodas, Wuji Cao, Crystal Yuri Oh, Amanda Jiang, Atiq Nurani, Danni Y. Zhu, Girija Goyal, Sarah E. Gilpin, Rachelle Prantil-Baun, Donald E. Ingber
bioRxiv 2020.04.13.039917; doi: https://doi.org/10.1101/2020.04.13.039917
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Human organs-on-chips as tools for repurposing approved drugs as potential influenza and COVID19 therapeutics in viral pandemics
Longlong Si, Haiqing Bai, Melissa Rodas, Wuji Cao, Crystal Yuri Oh, Amanda Jiang, Atiq Nurani, Danni Y. Zhu, Girija Goyal, Sarah E. Gilpin, Rachelle Prantil-Baun, Donald E. Ingber
bioRxiv 2020.04.13.039917; doi: https://doi.org/10.1101/2020.04.13.039917

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