Human Organ Chips Shift Amodiaquine from Older Antimalarials to Promising COVID-19 Treatment

As COVID-19 (New Coronavirus Infection) The pandemic continues and the pace of vaccine development is beyond anyone’s expectations. Unfortunately, therapeutic drug development is not keeping pace. To be sure, there are still few effective treatments for COVID-19. Currently, in collaboration with four laboratories, the antimalarial drug amodiaquine has been identified as a potent inhibitor of SARS-CoV-2 infection in human lung cells and living preclinical models. This breakthrough has helped ensure that the drug includes amodiaquine in ongoing COVID-19 clinical trials in 13 inexpensive and widely available African countries.

The study is published at Nature Biomedical Engineering In the treatise, “Human airway on-chip to quickly identify candidate antiviral and prophylactic agents.. “

Many groups around the world have used cultured cells to test existing drugs for efficacy against COVID-19, but dish-grown cells do not behave like living human cells and are . Many drugs that appear to be effective in room studies do not work in patients.

This collaboration is based on the Human OrganChip, which streamlines the process of assessing the safety and efficacy of existing drugs for new medical applications and provides a proof of concept for the rapid reuse of existing drugs using OrganChips. Drug testing ecosystem has been established. New medical applications, including future pandemics.

Most of these drugs (including hydroxychloroquine and chloroquine) are effective when a group of drugs previously shown to be effective in cell culture models are tested on more sophisticated microfluidic lung airway chips. It wasn’t. However, the antimalarial drug amodiaquine was very effective in preventing the invasion of the virus. These results were validated in a small animal model of COVID-19 using cultured cells and the infectious SARS-CoV-2 virus.

“The speed at which this team came together to move to COVID-19 and produce clinically significant results is amazing,” said Don Ingber, MD, and PhD, senior author and founding director of the Wyss Institute. .. “We started testing these compounds in February 2020, had the data available by March, and published a preprint in April. The openness and cooperation that pandemic caused in the scientific world. Thanks to this, our main drug is currently being tested in humans, which is a strong proof of Organ Chips’ ability to accelerate preclinical trials. “

More than three years ago, the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH) funded the Ingber team to faithfully mimic the functioning of human organs in vitro. We investigated whether culture technology is possible. Used to tackle the challenges of potential biological threats, including pandemic respiratory viruses.

The human airway chip developed by the Wyss team 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 grow in one channel that is perfused with air, and human vascular cells grow in the other channel that is perfused with liquid medium to mimic blood flow. Cells grown on this device spontaneously differentiate into multiple airway-specific cell types in proportions similar to the human airway, with the properties observed in living lungs such as cilia and the ability to produce and migrate mucus. To develop. Airway chip cells also have high levels of angiotensin converting enzyme-2 (ACE2) receptor protein. It plays a central role in the physiology of the lungs and is used to infect cells by SARS-CoV-2.

“The biggest challenge in shifting our focus to SARS-CoV-2 was the lack of a laboratory facility with the infrastructure needed to safely study dangerous pathogens. To avoid this problem, We designed a SARS-CoV-2 pseudovirus that expresses the SARS-CoV-2 spike protein, which allows us to identify agents that interfere with the ability of the spike protein to bind to the ACE2 receptor in human lung cells. “The Wis Institute’s post-doctor fellow and co-lead author of the study, said Dr. Haichinbai. “The second goal is for other OrganChip studies where these types of studies have this technology as well, but lack access to the laboratory facilities needed to study highly infectious viruses. It was to demonstrate that it could be done by a person. “

Armed with a fake virus that allowed them to study SARS-CoV-2 infection, the team first approved several approvals, including amodiaquine, toremifene, clomiphene, chloroquine, hydroxychloroquine, albidol, verapamil, amiodarone. The drug was used to perfuse the vascular channels of Airway Chips. All of these have been shown to be active against other related viruses in previous studies. However, in contrast to static culture studies, they use clinically appropriate doses to channel the chips to mimic how the drug is distributed to the tissues of our body. I was able to perfuse the drug through. Twenty-four hours later, they introduced the SARS-CoV-2 pseudovirus into the respiratory tract of Airway Chips, mimicking infection by aerial viruses such as coughing and sneezing.

Of these drugs, only three, amodiaquine, toremifene, and clomiphene, significantly prevented the invasion of the virus without damaging the airway chips. The most powerful drug, amodiaquine, reduced infection by about 60%. The team also performed spectroscopic measurements to assess how the drug affected airway cells. These studies show that amodiaquine produces clearer and broader protein changes than other antimalarial drugs.

Despite Amodiaquine’s promise, the team needed to demonstrate that it works against the actual infectious SARS-CoV-2 virus. Ingber collaborated with Dr. Matthew Frieman, an associate professor at the University of Maryland School of Medicine, and Dr. Benjamin ten Oever, a professor at Mount Sinai School of Medicine. Both have already set up biosafety laboratories to study infectious pathogens.

Freeman Institute tests amodiaquine and its active metabolite, desethylamodiaquine, against native SARS-CoV-2 by high-throughput assay in vitro cells and the drug inhibits viral infection. I confirmed that.

In parallel, the tenOever lab tested amodiaquine and hydroxychloroquine against native SARS-CoV-2 in a direct comparison with a small animal COVID-19 model, and prophylactic treatment with amodiaquine reduced viral load by approximately 70%. I confirmed that I would do it. Upon exposure, hydroxychloroquine had no effect. They also found that amodiaquine was effective in preventing the transmission of the virus from disease to healthy animals for more than 90% of the time and reducing the viral load when administered after the introduction of the virus. .. Therefore, their results suggest that amodiaquine may function in both therapeutic and prophylactic modes.

“It was very exciting to see how amodiaquine beautifully suppressed airway chip infections,” Freeman said. “And the fact that it appears to work both before and after exposure to SARS-CoV-2 means that it can be potentially effective in a wide variety of settings.”

The preprint of the result of Amodiaquine Published online On April 15, 2020, it became a hot topic in the scientific community. The results, along with studies from several other groups, contributed to the inclusion of amodiaquine in clinical trials in collaboration with the University of the Witwatersrand in South Africa and Simpoon Pharmaceuticals in South Korea. A few months later, the Neglected Disease Drug Initiative (DNDi) added amodiaquine to the COVID-19 ANTICOV clinical trial, which spans 19 sites in more than 13 African countries.

The identification of amodiaquine is a great boon in the fight against COVID-19, but the team is already looking to future pandemics. In addition to SARS-CoV-2, their recent publication details the successful finding of drugs that can protect or treat several strains of the influenza virus.

“Thanks to our experience testing COVID-19 amodiaquine using this drug development pipeline, we are now applying what we have learned to influenza and other pandemic-causing pathogens,” co-authored. Dr. Ken Carlson said. Helps lead the Wyss Institute’s Coronavirus Treatment Project Team. “This process gives us confidence that Organ Chips can predict what will be seen in more complex biological models of viral infections, and will leverage the Wyss Institute’s creative cauldron to integrate and enhance treatment discovery engines. I was able to.”