One of the first focuses of organ-chip specialist Emulate (Boston) was to reduce the need for animal testing over time. Its technology can simulate tissue-tissue interfaces within organs using human cells.
But the potential of the organ chips to yield mechanistic insights for drug discovery and understanding toxicities has become more evident over time.
The pandemic has underscored that promise, highlighting the potential of Emulate’s technology for drug discovery and vaccine testing.
A spinout of the Wyss Institute for Biologically Inspired Engineering at Harvard University, Emulate has developed a human airway chip culture that was highlighted earlier this year in Nature Biomedical Engineering.
Created with microchip manufacturing techniques and microfluidic culture technology, Emulate’s organ chips contain living human cells that simulate organ-level functions. The organ chips can “recreate tissue-tissue interfaces, which is what defines an organ,” said Dr. Donald E. Ingber, scientific founder of Emulate and chairman of its scientific advisory board.
Dr. Don Ingber
Emulate’s roots trace back to 2010 with the publication in Science focused on a human breathing lung-on-a-chip. The device was “really a model of the alveolus,” Ingber said in the webinar. The chip was used for “modeling virus evolution and rapid drug repurposing with a human airway lung-chip,” he added.
Since then, Emulate has created more sophisticated large airway chips that can simulate viral infections.
Before the pandemic, Emulate had been using its airway chip models of viral infection to study influenza. “Both NIH and DARPA funded our group with the idea of developing models to study potential pandemic viruses,” Ingber said. The company studied strain-dependent virulence in H1N1, H3N2 and H5N1 virus subtypes.
The models can mimic infection as well as injury to the epithelium. “But probably what’s most important is we can model the inflammatory responses in response to drugs,” Ingber said.
The lung chip can also provide a means to study viral evolution resulting from mutation or gene reassortment.
In 2020 when the SARS-CoV-2 pandemic began ramping up, Emulate began testing its bronchial-airway-on-a-chip to test the impact of existing drugs on a pseudotyped SARS-CoV-2 virus. In particular, they tested the therapeutic effects of amodiaquine, toremifene, clomiphene, chloroquine, hydroxychloroquine, arbidol, verapamil and amiodarone in the airway-on-a-chip experiment.
When testing the chips, rather than bathing a chip in drug, Emulate used clinically relevant doses. In the experiments, the researchers used the blood Cmax, the maximum drug concentration observed in the sampled blood.
“Hydroxychloroquine and chloroquine we’re not active, which is what has been confirmed in every study since,” Ingber said. “Arbidol, verapamil and amiodarone, which went to clinical trials, [also] were not active.”
The researchers found three drugs had some level of activity, with the malaria drug amodiaquine showing the most.
Working with partners, Emulate and colleagues at the Wyss Institute confirmed that amodiaquine did inhibit infectious SARS-CoV-2 in a Biosafety Level 3 (BSL-3) lab.
Amodiaquine also had a significant reduction in viral load in a hamster model. “We had an animal transmission model, which showed inhibition by over 90%,” Ingber said. The drug also showed promise in a treatment model. “And this drug [amodiaquine] is now in clinical trials across 20 sites in Africa, in part because of these results,” Ingber said.
Emulate customized its molecular dynamics simulation approach to model for the opening of the spike protein.
After that, the researchers designed a compound that went on to show promise in the pseudotyped virus assay. They also identified existing drugs that bind to the same site.
From there, the scientists used Emulate’s molecular dynamics simulation to “create versions of these existing drugs that don’t have the known activity of the drug but would bind even better to our site,” Ingber said.
Emulate is also using an iterative approach that combines machine learning and biological testing before validating the drugs in human organ chips.
“This is all a work in progress: We now have a lead compound that inhibits the Alpha, Beta, Delta and Gammas strains of SARS-CoV-2 equally in the 1 μM range,” Ingber said. “The same compound inhibits SARS-CoV-2 in MERS in the nM range.”
Filed Under: Infectious Disease
