Cambridge University researchers have found that a previously unpatented drug may be effective in preventing COVID-19 and potentially protecting against future variants of the virus. The discovery was made through a combination of experiments using mini-organs, donor organs, animal studies and patient data.
Unique experiments involved “mini-organs”, animal research, human organ donations, volunteers and patients.
- Cambridge scientists have shown that a drug widely used to treat liver disease can prevent[{” attribute=””>SARS-CoV-2 infection or reduce
Cambridge scientists have identified an off-patent drug that can be repurposed to prevent COVID-19 – and may be able to protect against future variants of the virus – in research involving a unique mix of ‘mini-organs’, donor organs, animal studies, and patients.
The research, recently published in the journal Nature, showed that an existing drug used to treat a type of liver disease is able to “lock” the door through which SARS-CoV-2 enters our cells, a receptor on the surface of cells called ACE2. Because this drug targets host cells and not the virus, it should protect against future new variants of the virus as well as other coronaviruses that may emerge.
If confirmed in larger clinical trials, it could provide an essential drug to protect people for whom vaccines are ineffective or inaccessible as well as people at increased risk of infection.
Dr Fotios Sampaziotis, from the University of Cambridge’s Wellcome-MRC Cambridge Stem Cell Institute and Addenbrooke’s Hospital, led the research in collaboration with Professor Ludovic Vallier from the Berlin Health Institute at Charité.
Bile duct/hepatic organoid infected with SARS-CoV-2 – red indicates virus. Credit: Teresa Brevini
Dr Sampaziotis said: “Vaccines protect us by strengthening our immune system so that it can recognize the virus and eliminate it, or at least weaken it. But vaccines don’t work for everyone – for example patients with weakened immune systems – and not everyone has access to them. Also, the virus can mutate into new vaccine-resistant variants.
“We are interested in finding other ways to protect against SARS-CoV-2 infection that do not rely on the immune system and that could complement vaccination. We have discovered a way to close the door to the virus, preventing it from entering our cells and protecting us from infection.
Mini-organs and animals…
Dr. Sampaziotis previously worked with organoids – “mini bile ducts” – to study bile duct diseases. Organoids are clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same functions as the part of the organ being studied.
Using them, the researchers discovered – rather by chance – that a molecule known as FXR, which is present in large quantities in these bile duct organoids, directly regulates the viral ACE2 “door”, opening it and closing it effectively. They then showed that ursodeoxycholics[{” attribute=””>acid
(UDCA), an off-patent drug used to treat a form of liver disease known as primary biliary cholangitis, ‘turns down’ FXR and closes the ACE2 doorway.
Perfused lung. Credit: Teresa Brevini
In this new study, his team showed that they could use the same approach to close the ACE2 doorway in ‘mini-lungs’ and ‘mini-guts’ – representing the two main targets of SARS-CoV-2 – and prevent viral infection.
The next step was to show that the drug could prevent infection not only in lab-grown cells but also in living organisms. For this, they teamed up with Professor Andrew Owen from the University of Liverpool to show that the drug prevented infection in hamsters exposed to the virus, which are used as the ‘gold-standard’ model for pre-clinical testing of drugs against SARS-CoV-2. Importantly, the hamsters treated with UDCA were protected from the delta variant of the virus, which was new at the time and was partially resistant to existing vaccines.
Professor Owen said: “Although we will need properly-controlled randomized trials to confirm these findings, the data provide compelling evidence that UDCA could work as a drug to protect against COVID-19 and complement vaccination programs, particularly in vulnerable population groups. As it targets the ACE2 receptor directly, we hope it may be more resilient to changes resulting from the evolution of the SARS-CoV-2 spike, which result in the rapid emergence of new variants.”
… to human organs…
Next, the researchers worked with Professor Andrew Fisher from Newcastle University and Professor Chris Watson from Addenbrooke’s hospital to see if their findings in hamsters held true in human lungs exposed to the virus.
The team took a pair of donated lungs not suitable for transplantation, keeping them breathing outside the body with a ventilator and using a pump to circulate blood-like fluid through them to keep the organs functioning while they could be studied. One lung was given the drug, but both were exposed to SARS-CoV-2. Sure enough, the lung that received the drug did not become infected, while the other lung did.
Professor Fisher said: “This is one of the first studies to test the effect of a drug in a whole human organ while it’s being perfused. This could prove important for organ transplantation – given the risks of passing on COVID-19 through transplanted organs, it could open up the possibility of treating organs with drugs to clear the virus before transplantation.”
… to people
Moving next to human volunteers, the Cambridge team collaborated with Professor Ansgar Lohse from the University Medical Centre Hamburg-Eppendorf in Germany.
Professor Lohse explained: “We recruited eight healthy volunteers to receive the drug. When we swabbed the noses of these volunteers, we found lower levels of ACE2, suggesting that the virus would have fewer opportunities to break into and infect their nasal cells – the main gateway for the virus.”
While it wasn’t possible to run a full-scale clinical trial, the researchers did the next best thing: looking at data on COVID-19 outcomes from two independent cohorts of patients, comparing those individuals who were already taking UDCA for their liver conditions against patients not receiving the drug. They found that patients receiving UDCA were less likely to develop severe COVID-19 and be hospitalized.
A safe, affordable variant-proof drug
First author and PhD candidate Teresa Brevini from the University of Cambridge said: “This unique study gave us the opportunity to do really translational science, using a laboratory finding to directly address a clinical need.
“Using almost every approach at our fingertips we showed that an existing drug shuts the door on the virus and can protect us from COVID-19. Importantly, because this drug works on our cells, it is not affected by mutations in the virus and should be effective even as new variants emerge.”
Dr. Sampaziotis said the drug could be an affordable and effective way of protecting those for whom the COVID-19 vaccine is ineffective or inaccessible. “We have used UDCA in clinic for many years, so we know it’s safe and very well tolerated, which makes administering it to individuals with high COVID-19 risk straightforward.
“This tablet costs little, can be produced in large quantities fast and easily stored or shipped, which makes it easy to rapidly deploy during outbreaks – especially against vaccine-resistant variants, when it might be the only line of protection while waiting for new vaccines to be developed. We are optimistic that this drug could become an important weapon in our fight against COVID-19.”
Reference: “FXR inhibition may protect against SARS-CoV-2 infection by reducing ACE2” by Teresa Brevini, Mailis Maes, Gwilym J. Webb, Binu V. John, Claudia D. Fuchs, Gustav Buescher, Lu Wang, Chelsea Griffiths, Marnie L. Brown, William E. Scott III, Pehuén Pereyra-Gerber, William TH Gelson, Stephanie Brown, Scott Dillon, Daniele Muraro, Jo Sharp, Megan Neary, Helen Box, Lee Tatham, James Stewart, Paul Curley, Henry Pertinez, Sally Forrest, Petra Mlcochova, Sagar S. Varankar, Mahnaz Darvish-Damavandi, Victoria L. Mulcahy, Rhoda E. Kuc, Thomas L. Williams, James A. Heslop, Davide Rossetti, Olivia C. Tysoe, Vasileios Galanakis, Marta Vila-Gonzalez, Thomas WM Crozier, Johannes Bargehr, Sanjay Sinha, Sara S. Upponi, Corrina Fear, Lisa Swift, Kourosh Saeb-Parsy, Susan E. Davies, Axel Wester, Hannes Hagström, Espen Melum, Darran Clements, Peter Humphreys, Jo Herriott, Edyta Kijak, Helen Cox, Chloe Bramwell, Anthony Valentijn, Christopher JR Illingworth, research consortium e UK-PBC, Bassam Dahman, Dustin R. Bastaich, Raphaella D. Ferreira, Thomas Marjot, Eleanor Barnes, Andrew M. Moon, Alfred S. Barritt IV, Ravindra K. Gupta, Stephen Baker, Anthony P. Davenport, Gareth Corbett , Vassilis G. Gorgoulis, Simon JA Buczacki, Joo-Hyeon Lee, Nicholas J. Matheson, Michael Trauner, Andrew J. Fisher, Paul Gibbs, Andrew J. Butler, Christopher JE Watson, George F. Mells, Gordon Dougan, Andrew Owen , Ansgar W. Lohse, Ludovic Vallier and Fotios Sampaziotis, December 5, 2022, Nature.
DOI: 10.1038/s41586-022-05594-0The research was largely funded by UK Research & Innovation, the European Association for the Study of the Liver, the NIHR Cambridge Biomedical Research Center and Evelyn Trust.
