A Wyss Institute-led collaboration spanning four research labs and hundreds of miles has used the institute’s organ-on-a-chip (Organ Chip) technology to identify the antimalarial drug amodiaquine as a potent inhibitor of infection with SARS-CoV-2, the virus that causes COVID-19.
The Organ Chip-based drug testing ecosystem established by the collaboration greatly 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. The research is reported in Nature Biomedical Engineering.
While many groups around the world have been testing existing drugs for efficacy against COVID-19 using cultured cells, it is well known that 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 Wyss team examined eight existing drugs, including hydroxychloroquine and chloroquine, that they and others had found were active against SARS-CoV-2 in conventional cell culture assays.
When tested in their more sophisticated microfluidic Lung Airway Chip, which had been infected with a pseudotyped SARS-CoV-2 virus, they found that most of these drugs, including hydroxychloroquine and chloroquine, were not effective. However, another 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. Amodiaquine is now in clinical trials for COVID-19 at multiple sites in Africa, where this drug is inexpensive and widely available.
“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. “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.”
From mysterious disease to lead compound in months
In the early months of the COVID-19 pandemic when little was known about the novel SARS-CoV-2 virus, efforts were made around the globe to identify existing drugs that could be repurposed to treat patients who were falling ill. While early data performed on cells grown in lab dishes seemed to suggest that the antimalarial drugs chloroquine and hydroxychloroquine could treat the disease, later studies showed that they aren’t active against SARS-CoV-2 in animals or patients, and the quest for an effective oral therapeutic that can both treat and prevent COVID-19 continues.
Fortunately, the Wyss Institute had a ready-made solution to that problem. In a move that today seems prescient, 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.
Two years into the project, the team was making steady progress using its lung Airway Chip to study drugs that could be repurposed to treat influenza virus infections. Then, in January 2020, first authors Longlong Si and Haiqing Bai heard about cases of what was being called a novel viral pneumonia in China.
“That caught a lot of scientists’ attention, because any new virus could become a global threat given how easily infections spread in today’s era of widespread international travel. We closely followed the updates because we thought that our Airway Chip model could provide an important tool for studying this virus,” said Si, a Wyss technology development fellow and co-lead author. Once it became clear that people were falling ill due to the mysterious COVID-19 and not pneumonia, the team quickly shifted its focus to the novel SARS-CoV-2 virus.