The off-patent drug that could protect us from future COVID-19 variants

Dr Sampaziotis had previously been working with organoids – ‘mini-bile ducts’ – to study diseases of the bile ducts. 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 these, the researchers found – rather serendipitously – that  a molecule known as FXR, which is present in large amounts in these bile duct organoids, directly regulates the viral ‘doorway’ ACE2, effectively opening and closing it. They went on to show that ursodeoxycholic 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.

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.

“Although we will need properly-controlled randomised 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 programmes, particularly in vulnerable population groups.”

^{Professor Andrew Owen, University of Liverpool}

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.

“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.”

^{Professor Andrew Fisher, Newcastle University}

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.”

^{Teresa Brevini, University of Cambridge}

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.”