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Human Organ Chips "Promising COVID-19 Treatment"

The rate of vaccine production has exceeded anyone's wildest expectations as the COVID-19 pandemic continues. Unfortunately, treatment drug progress has not kept up with the pace. COVID-19 is still a disease with few available therapies. The antimalarial drug amodiaquine has now been established as a potent inhibitor of SARS-CoV-2 infection in human lung cells and in living preclinical models, thanks to a collaboration between four research institutes. This discovery paved the way for amodiaquine to be included in the COVID-19 clinical trial, which is currently taking place in 13 African countries where the medication is cheap and readily 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.”

Although many organizations around the world have used cultured cells to test existing drugs for effectiveness against COVID-19, cells grown in a dish do not act the same way as cells in a living human body, and many drugs that appear to be successful in lab trials do not function in patients.

The partnership created a human Organ Chip-based drug testing ecosystem that streamlines the process of assessing the safety and effectiveness of existing drugs for new medical applications, as well as a proof-of-concept for using Organ Chips to quickly repurpose existing drugs for new medical applications, such as potential pandemics.

When a group of drugs that had previously been shown to be successful in cell culture models were tested in the more advanced microfluidic Lung Airway Chip, the majority of them (including hydroxychloroquine and chloroquine) were found to be ineffective. The antimalarial drug amodiaquine, on the other hand, was very effective at preventing viral entry. These findings were then confirmed using infectious SARS-CoV-2 virus in cultured cells and a small animal model of COVID-19.

Don Ingber, MD, PhD, senior author and Wyss Institute Founding Director, said, "The pace at which this team assembled, pivoted to COVID-19, and achieved clinically important results is astonishing." “In February 2020, we began testing these compounds, had data by March, and released a preprint in April. Our lead drug is now being tested in humans, thanks to the transparency and cooperation that the pandemic has ignited within the scientific community. It's a strong endorsement of Organ Chips' ability to speed up preclinical testing.”

Ingber's team received funding from the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH) over three years ago to investigate whether its human Organ Chip microfluidic culture technology, which faithfully mimics the operation of human organs in vitro, could be used to combat biothreat challenges such as pandemic respiratory viruses.

The Wyss team's human Airway Chip is a microfluidic device the size of a USB memory stick that comprises two parallel channels separated by a porous membrane for these studies. Human lung airway cells are grown in one channel that receives air, while human blood vessel cells are grown in another channel that receives liquid culture medium to simulate blood flow. Cells developed in this system naturally differentiate into several airway-specific cell types in proportions identical to those found in the human airway, and develop cilia and the capacity to generate and transport mucus, as seen in living lungs. Access to the lungs Chip cells also have higher levels of the angiotensin-converting enzyme-2 (ACE2) receptor protein, which is used by SARS-CoV-2 to infect cells and plays a key role in lung physiology.

“The fact that we don't have lab facilities with the requisite infrastructure to safely research dangerous pathogens was our biggest challenge in turning our attention to SARS-CoV-2. To get around this, we created a SARS-CoV-2 pseudovirus that expressed the SARS-CoV-2 spike protein so that we could find drugs that interfere with the spike protein's ability to bind to the ACE2 receptors in human lung cells,” said Haiqing Bai, PhD, a postdoctoral fellow at the Wyss Institute and co-lead author on the report. “An additional aim was to show that these types of studies could be carried out by other Organ Chip researchers who have access to the same technology,”  However, they do not have access to the lab facilities required to research highly infectious viruses.”

The team used the SARS-CoV-2 pseudovirus to perfuse the Airway Chips' blood vessel channel with several approved drugs, including amodiaquine, toremifene, clomiphene, chloroquine, hydroxychloroquine, arbidol, verapamil, and amiodarone, which have all shown activity against other associated viruses in previous studies. They were able to perfuse the drug across the channels of the chip using a clinically relevant dosage to simulate how the drug would be administered to tissues in our bodies, as opposed to static culture experiments. They inserted SARS-CoV-2 pseudovirus into the Airway Chips' air channel after 24 hours to imitate infection by airborne viruses, such as those found in coughs and sneezes.

Just three of these drugs, amodiaquine, toremifene, and clomiphene, substantially reduced viral entry in the Airway Chips without causing cell damage. Amodiaquine, the most powerful medicine, reduced infection by around 60%. The researchers have used spectrometry to see how the drugs affected the airway cells. Amodiaquine caused distinct and wider protein changes than the other antimalarial drugs, according to these findings.

Despite amodiaquine's promise, the team still needed to show that it was effective against the real SARS-CoV-2 virus. Ingber collaborated with Matthew Frieman, PhD, associate professor of medicine at the University of Maryland, and Benjamin tenOever, PhD, professor of medicine at Mount Sinai's Icahn School of Medicine, who both had biosafety labs set up to research infectious pathogens.

The Frieman lab used high-throughput assays in cells in vitro to test amodiaquine and its active metabolite, desethylamodiaquine, against native SARS-CoV-2, and found that the drug prevented viral infection.

In a head-to-head analysis of amodiaquine and hydroxychloroquine against native SARS-CoV-2 in a small animal COVID-19 model, the tenOever lab discovered that prophylactic treatment with amodiaquine resulted in a 70% reduction in viral load upon exposure, while hydroxychloroquine was ineffective. They also discovered that amodiaquine was effective in reducing viral load when provided after the virus was introduced, and that it stopped the virus from spreading from sick to healthy animals in more than 90% of cases. As a result, their findings indicate that amodiaquine may be used for both treatment and prevention.

“It was thrilling to see how well amodiaquine prevented infection in the Airway Chip,” Frieman said. “Moreover, the fact that it appears to function both before and after exposure to SARS-CoV-2 suggests that it may be useful in a number of situations.”

On April 15, 2020, a preprint of the amodiaquine findings was released online, causing a stir in the scientific community. Amodiaquine was used in a clinical trial last fall in conjunction with the University of Witwatersrand in South Africa and Shin Poong Pharmaceutical in South Korea, thanks to the findings and those of many other parties. A few months later, the Drugs for Neglected Diseases Initiative (DNDi) added amodiaquine to COVID-19's ANTICOV clinical trial, which covers 19 sites in 13 African countries.

Although the discovery of amodiaquine is a significant step forward in the battle against COVID-19, the team is already looking forward to future pandemics. Their recent publication outlines their success in discovering drugs that could protect against or treat many strains of influenza virus, in addition to SARS-CoV-2.

“We are now applying what we learned by using this drug discovery pipeline to confirm amodiaquine for COVID-19 to influenza and other pandemic-causing pathogens,” said co-author Ken Carlson, PhD, a lead senior staff scientist who helps lead the Wyss Institute's Coronavirus Therapeutic Project Team. “This method has provided us faith that Organ Chips will predict what we see in more complex living models of viral infections, and it has assisted us in harnessing the Wyss Institute's innovative cauldron to consolidate and improve our therapeutic discovery engine.”

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