Human organ chip-enabled pipeline to rapidly repurpose therapeutics during viral pandemics

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 These Airway was not certified by peer review) Chips, which contain human lung epithelial cells that express high levels of ACE2 and TMPRSS2, were then used to assess the inhibitory activities of 7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. ______________________________________________________________________The increasing incidence of potentially pandemic viruses, such as influenza, MERS, SARS, and now SARS-CoV-2, requires development of new preclinical approaches that can accelerate development of effective therapeutics and prophylactics. The most rapid way to confront a pandemic challenge would be to repurpose existing drugs that are approved for other medical applications as anti-viral therapeutics. While clinicians around the world are attempting to do this for the COVID19 pandemic, the current approaches have been haphazard, which have resulted in equivocal results regarding drug efficacies and possible toxicity risks as in the case of chloroquine 1-3 ; thus, there is a great need to attack this problem in a was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.

Shotgun proteomics of SARS-CoV-2 infected cells and its application to the optimisation of whole viral particle antigen production for vaccines

“…We can anticipate that the same workflow could be successfully applied to expedite the characterisation of human organ-on-a-chip (Organ Chip) microfluidic culture devices used to obtain insights on the different steps of the virus life cycle as well as to study human disease pathogenesis [27] in response to infection by variants of SARS-Cov-2 under or not the addition of existing [28,29,30] and novel therapeutics.…”

Is it Time for Reviewer 3 to Request Human Organ Chip Experiments Instead of Animal Validation Studies?

“…Most recently, an influenza virus infection model was developed using the Lung Airway Chip, which replicates the virulence of different viral strains (e.g., H1N1 vs H3N2 and H5N1) and enables quantification of host cytokine and immune cell responses, as well as mimicry of clinical responses to antiviral therapies and spontaneous viral evolution in response to drug exposure that is enabled by human-to-human transmission. [20,21] Microfluidic Airway Chips are now being used to model human lung infection by SARS-CoV-2 virus in vitro, and to repurpose existing FDAapproved drugs as potential COVID-19 therapeutics. [21,22] Importantly, it is extremely difficult to develop animal models of viral infection, and none replicate human host responses as well as these Organ Chip models that incorporate highly differentiated human lung cells grown under an ALI while exposed to dynamic fluid flow at their base.…”

“…[20,21] Microfluidic Airway Chips are now being used to model human lung infection by SARS-CoV-2 virus in vitro, and to repurpose existing FDAapproved drugs as potential COVID-19 therapeutics. [21,22] Importantly, it is extremely difficult to develop animal models of viral infection, and none replicate human host responses as well as these Organ Chip models that incorporate highly differentiated human lung cells grown under an ALI while exposed to dynamic fluid flow at their base.…”

Emerging preclinical evidence does not support broad use of hydroxychloroquine in COVID-19 patients

“…Multiple FDA approved drugs that had been shown to inhibit SARS-CoV-2 in Vero cells by different groups, including CQ, were tested using SARS-CoV-2 pseudoviruses (lentivirus particles pseudotyped with the SARS-CoV-2 spike protein) in the Emulate human lung-chips 5 . When flowing the drugs through lung-chip devices, at a clinically relevant dose (the reported human Cmax) to mimic how drugs are delivered to organs in our bodies, CQ did not produce statistically significant inhibition of replication of the SARS-CoV-2 Spike pseudotyped viruses.…”