A Cheap, readily available drug used to treat a liver disease called primary biliary cholangitis could prevent Covid-19 blocking all variants of the Sars-CoV-2 virus – present and future – from entering the cells of the target organs. A new possibility of using ursodeoxycholic acid (Udca), an off-patent medicine that is taken by mouth, is proposed by a study published in ‘Nature’ by a team of scientists coordinated by Fotios Sampaziotis of the Wellcome-Mrc Cambridge Stem Cell Institute of Cambridge University and Addenbrooke Hospital (UK), in collaboration with Ludovic Vallier of the Berlin Institute of Health at Charité (Germany).
The work involved organoids (miniaturized models of organs manufactured in a laboratory), animals, human organs and a small group of healthy volunteers. And if the results are confirmed in larger clinical trials, according to the authors, the UDCA could support vaccines by offering an effective ‘shield’ also to patients for whom vaccination does not work or is inaccessible, as well as to people at greater risk of infection . “We have found a way to close the door to the virus, preventing it from entering our cells and protecting us from contagion,” explains Sampaziotis. Since Udca acts not on the virus, but on the Ace2 cell receptor that Sars-CoV-2 exploits to enter target cells, the drug could be effective regardless of the variant of the pandemic coronavirus.
It all started with some research by the Sampaziotis group who, to study the pathologies of the bile ducts, had built ‘mini ducts’ capable of reproducing the functions of the natural ones. His team had thus discovered almost fortuitously that a molecule known as Fxr, present in large quantities in bile duct organoids, directly regulates the opening or closing state of Ace2. Scientists have therefore demonstrated that Udca ‘turns off’ Fxr transforming Ace2 into an ‘armored door’. In this new work, Sampaziotis and colleagues used the same approach to shut down Ace2 in miniaturized models of lung or intestine, two of the preferred targets of SARS-CoV-2, and prevent viral infection. The experiment was successful and the researchers took the next steps.
From organoids, the scholars first moved on to animals: together with Andrew Owen of the University of Liverpool (UK) they confirmed that Udca is able to prevent infection in hamsters exposed to Sars-CoV-2. After the animals, man. First, working with Andrew Fisher of the University of Newcastle (UK) and Chris Watson of Addenbrooke’s hospital, the scientists verified their results on two human lungs taken from cadavers and not suitable for transplantation: by keeping them viable and ‘breathing’, they treated one with the drug and put both in contact with the virus, observing that the ‘control’ lung became infected while the treated one did not.
Finally, the tests on human volunteers, carried out in collaboration with Ansgar Lohse of the Hamburg-Eppendorf University Medical Center, in Germany: the Udca was administered to 8 healthy people, in whose nasal swabs lower levels of Ace2 were actually found, suggest that the virus would be less likely to infect them. Although it was not possible to conduct a large-scale clinical trial, the researchers investigated the ‘Covid status’ of two groups of patients: one received the drug because it was suffering from primary biliary cholangitis, the other did not take it. It thus emerged that patients in the ‘Udca group’ were less likely to develop severe Covid-19 and be hospitalized.
“This unique study – says first author Teresa Brevini, PhD candidate at the University of Cambridge – gave us the opportunity to really do translational science”, from the counter to the bedside, “exploiting a laboratory discovery to try to answer a a clinical need. Using almost all the possible approaches at our disposal, we have shown that an already available drug closes the gateway to the virus and can protect us from Covid-19. It is important to emphasize that, since this drug acts on our cells” and not on the virus, “is unaffected by viral mutations and should remain effective as new variants emerge.”
According to Sampaziotis, this old drug could therefore offer in the future an effective and low-cost strategy to protect people in whom the vaccine does not work or who cannot access it from Sars-CoV-2 infection. “We have been using Udca in the clinic for many years – remarks the author of the work, funded largely by UK Research & Innovation, the European Association for the Study of the Liver, the Nihr Cambridge Biomedical Research Center and the Evelyn Trust – so we know that it is safe and very well tolerated, making it simple to administer to high-risk Covid patients.”
“This tablet costs little – adds Sampaziotis – The drug can be produced quickly in large quantities and stored easily, which makes it easy to distribute quickly in the event of a pandemic especially against vaccine-resistant viral variants, when it could be the only line of protection pending development of new vaccines” updated. “We are optimistic – concludes the scientist – that this drug could become an important weapon in our fight against Covid-19”.
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