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Human Organ Chips Shift Amodiaquine from Old Antimalarial to Promising COVID-19 Treatment

As the COVID-19 pandemic continues, the pace of vaccine development has surpassed anyone’s wildest expectations. Unfortunately, drug development for treatments has not kept the same pace. Indeed, there are still very few effective treatments for COVID-19. Now, a collaboration between four research institutes has identified the antimalarial drug amodiaquine as a potent inhibitor of SARS-CoV-2 infection in human lung cells and in living preclinical models. This breakthrough helped secure the inclusion of amodiaquine in a COVID-19 clinical trial that is currently underway in 13 different countries in Africa where this drug is inexpensive and widely available.

The research is published in Nature Biomedical Engineering in the paper, “A human-airway-on-a-chip for the rapid identification of candidate antiviral therapeutics and prophylactics.”

While many groups around the world have been testing existing drugs for efficacy against COVID-19 using cultured cells, cells grown in a dish do not behave like the cells in a living human body, and many drugs that appear effective in lab studies do not work in patients.

The collaboration established a human Organ Chip-based drug testing ecosystem that streamlines the process of evaluating the safety and efficacy of existing drugs for new medical applications, and provides a proof-of-concept for the use of Organ Chips to rapidly repurpose existing drugs for new medical applications, including future pandemics.

When a group of drugs that had been shown previously to have efficacy in cell culture models, were tested in the more sophisticated microfluidic Lung Airway Chip, most of these drugs (including hydroxychloroquine and chloroquine) were not effective. However, the antimalarial drug amodiaquine was highly effective at preventing viral entry. These results were then validated in cultured cells and in a small animal model of COVID-19 using infectious SARS-CoV-2 virus.

“The speed with which this team assembled, pivoted to COVID-19, and produced clinically significant results is astonishing,” said senior author and Wyss Institute Founding Director Don Ingber, MD, PhD. “We started testing these compounds in February 2020, had data by March, and published a preprint in April. Thanks to the openness and collaboration that the pandemic has sparked within the scientific community, our lead drug is now being tested in humans. It’s a powerful testament to Organ Chips’ ability to accelerate preclinical testing.”

Over three years ago the Defense Advanced Research Projects Agency (DARPA) and National Institutes of Health (NIH) awarded funding to Ingber’s team to explore whether its human Organ Chip microfluidic culture technology, which faithfully mimics the function of human organs in vitro, could be used to confront potential biothreat challenges including pandemic respiratory viruses.

The human Airway Chip that the Wyss team developed for these studies is a microfluidic device about the size of a USB memory stick that contains two parallel channels separated by a porous membrane. Human lung airway cells are grown in one channel that is perfused with air, while human blood vessel cells are grown in the other channel, which is perfused with liquid culture medium to mimic blood flow. Cells grown in this device naturally differentiate into multiple airway-specific cell types in proportions that are similar to those in the human airway, and develop traits observed in living lungs such as cilia and the ability to produce and move mucus. Airway Chip cells also have higher levels of angiotensin-converting enzyme-2 (ACE2) receptor protein, which plays a central role in lung physiology and is used by SARS-CoV-2 to infect cells.

The human Airway Chip recreates the interface of the human lung’s airways and blood vessels, allowing researchers to study how different drugs and pathogens like viruses affect lung function. [Wyss Institute at Harvard University]

“Our biggest challenge in shifting our focus to SARS-CoV-2 was that we don’t have lab facilities with the necessary infrastructure to safely study dangerous pathogens. To get around that problem, we designed a SARS-CoV-2 pseudovirus that expresses the SARS-CoV-2 spike protein, so that we could identify drugs that interfere with the spike protein’s ability to bind to human lung cells’ ACE2 receptors,” said Haiqing Bai, PhD, a postdoctoral fellow at the Wyss Institute and co-lead author on the study. “A secondary goal was to demonstrate that these types of studies could be carried out by other Organ Chip researchers who similarly have this technology, but lack access to lab facilities required to study highly infectious viruses.”

Armed with the pseudovirus that allowed them to study SARS-CoV-2 infection, the team first perfused the Airway Chips’ blood vessel channel with several approved drugs, including amodiaquine, toremifene, clomiphene, chloroquine, hydroxychloroquine, arbidol, verapamil, and amiodarone, all of which have exhibited activity against other related viruses in previous studies. However, in contrast to static culture studies, they were able to perfuse the drug through the channels of the chip using a clinically relevant dose to mimic how the drug would be distributed to tissues in our bodies. After 24 hours they introduced SARS-CoV-2 pseudovirus into the Airway Chips’ air channel to mimic infection by airborne viruses, like that in a cough or sneeze.

Only three of these drugs—amodiaquine, toremifene, and clomiphene—significantly prevented viral entry without producing cell damage in the Airway Chips. The most potent drug, amodiaquine, reduced infection by about 60%. The team also performed spectrometry measurements to assess how the drugs impacted the airway cells. These studies revealed that amodiaquine produced distinct and broader protein changes than the other antimalarial drugs.

Immuno-fluorescent staining of the human Airway Chip reveals that the airway cells growing there develop numerous structures that are specific to lung cells, including cilia (yellow) and a membrane protein called ZO-1 that keeps cells attached to each other (purple). [Wyss Institute at Harvard University]

Despite the promise of amodiaquine, the team still needed to demonstrate that it worked against the real infectious SARS-CoV-2 virus. Ingber teamed up with Matthew Frieman, PhD, associate professor at the University of Maryland School of Medicine and Benjamin tenOever, PhD, professor at the Icahn School of Medicine at Mount Sinai, both of whom already had biosafety labs set up to study infectious pathogens.

The Frieman lab tested amodiaquine and its active metabolite, desethylamodiaquine, against native SARS-CoV-2 via high-throughput assays in cells in vitro, and confirmed that the drug inhibited viral infection.

In parallel, the tenOever lab tested amodiaquine and hydroxychloroquine against native SARS-CoV-2 in a head-to-head comparison in a small animal COVID-19 model, and saw that prophylactic treatment with amodiaquine resulted in ~70% reduction in viral load upon exposure, while hydroxychloroquine was ineffective. They also saw that amodiaquine prevented the transmission of the virus from sick to healthy animals more than 90% of the time, and that it was also effective in reducing viral load when administered after introduction of the virus. Thus, their results suggest that amodiaquine could work in both treatment and prevention modes.

“Seeing how beautifully amodiaquine inhibited infection in the Airway Chip was extremely exciting,” said Frieman. “And, the fact that it seems to work both before and after exposure to SARS-CoV-2 means that it could potentially be effective in a wide variety of settings.”

A preprint of the amodiaquine results was published online on April 15, 2020, which generated buzz in the scientific community. The results, along with studies from several other groups, contributed to amodiaquine’s inclusion in a clinical trial in collaboration with the University of Witwatersrand in South Africa and Shin Poong Pharmaceutical in South Korea last fall. A few months later, the Drugs for Neglected Diseases Initiative (DNDi) added amodiaquine to the ANTICOV clinical trial for COVID-19, which spans 19 sites in over 13 different countries in Africa.

While the identification of amodiaquine is a major boon in fighting COVID-19, the team already has their sights set on future pandemics. In addition to SARS-CoV-2, their recent publication details their success in finding drugs that could protect against or treat several strains of influenza virus.

“Thanks to our experience using this drug development pipeline to validate amodiaquine for COVID-19, we are now applying what we learned to influenza and other pandemic-causing pathogens,” said co-author Ken Carlson, PhD, a lead senior staff scientist who helps lead the Coronavirus Therapeutic Project Team at the Wyss Institute. “This process has given us confidence that Organ Chips are predictive of what we see in more complex living models of viral infections, and helped harness the creative cauldron of the Wyss Institute to consolidate and strengthen our therapeutic discovery engine.”

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