An existing drug used to treat liver disease can block the doorway through which SARS-CoV-2 enters the human body, claims Cambridge scientists in a Nature article published on December 5, 2022. If validated in human clinical trials, the drug could complement vaccination efforts and protect those individuals against the COVID-19 virus for whom vaccines are ineffective or inaccessible. Since the drug targets host cells and not the virus, it will likely protect against new viral variants.
Fotios Sampaziotis, MD, PhD, a scientist at the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge, said, “Vaccines protect us by boosting our immune system so that it can recognize the virus and clear it, or at least weaken it. But vaccines don’t work for everyone – for example patients with a weak immune system – and not everyone has access to them. Also, the virus can mutate to new vaccine-resistant variants.” Sampaziotis and Ludovic Vallier, PhD, from the Berlin Institute of Health at Charité are co-senior authors of the study.
Using organoids—3D clusters of cells that grow and proliferate to mimic organs in culture—of the lung, liver and gut, Sampaziotis and his team identified a receptor, FXR (farnesoid X receptor) that is abundant in bile duct organoids and directly regulates ACE2, the doorway through which SARS-CoV-2 enters humans.
The investigators then used the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA) to suppress FXR signaling and downregulate ACE2 expression in human lung, liver, and intestinal organoids and in the corresponding tissues in mice and hamsters. They found UDCA-mediated ACE2 downregulation reduced susceptibility to SARS-CoV-2 infection in cultured cells, in animal models and in human lungs and livers perfused outside the body (ex situ).
Andrew Owen, PhD, a scientist at the University of Liverpool and a co-author of the study showed that UDCA prevented infection in hamsters exposed to the delta variant. “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,” said Owen. “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.”
In collaboration with Andrew Fisher, MS, PhD, a professor at Newcastle University and Chris Watson, MS, a surgeon at Addenbrooke’s hospital, the team tested the efficacy of UDCA in human lungs exposed to the virus ex situ. The donated lungs used for the study were deemed unsuitable for transplantation and maintained outside the body on a ventilator for the duration of the experiment. One lung was administered UDCA, but both were exposed to SARS-CoV-2. The lung that received the drug did not become infected, while the other lung did.
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.”
The researchers also showed UDCA reduces ACE2 expression in the nasal lining in humans. In collaboration with Ansgar Lohse, MD, from the University Medical Centre Hamburg-Eppendorf in Germany, the team tested UDCA in eight healthy human volunteers. Lohse said, “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.”
Moreover, in a retrospective study, the authors show a correlation between treatment with UDCA and positive clinical outcomes following SARS-CoV-2 infection. Comparing data on COVID-19 outcomes in those individuals who were already taking UDCA for their liver conditions against patients not receiving the drug, the researchers found that patients receiving UDCA were less likely to develop severe COVID-19 and be hospitalized.
“We have used UDCA in clinics 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,” said Sampaziotis. “This tablet costs little, can be produced in large quantities fast and easily stored or shipped.” Sampaziotis and his team are optimistic that UDCA could help treat patients infected with SARS-CoV-2.
