Almost three years after the pandemic, we are still regularly recording hundreds of thousands of new cases of COVID every day around the world. In a new study involving a combination of miniature organ models, donor organs, animals and humans, we show that a drug used to treat liver disease could be repurposed to protect against COVID-19.
Vaccines are one of the most effective weapons in our pandemic response, but not everyone can benefit from them. COVID vaccines work by training our immune system to recognize and destroy SARS-CoV-2, the virus that causes COVID-19. As such, they are not effective in people with poorly functioning immune systems, such as patients taking immune-suppressing drugs after an organ transplant.
The virus can also disguise itself from the immune system by mutating into new variants, thereby reducing the effectiveness of the vaccine.
Finally, vaccines are not equally accessible, with only one in four people in low-income countries having received at least one dose.
In light of these challenges, we wanted to develop a strategy to protect against COVID-19 that could complement vaccination. We decided to target the “door” that SARS-CoV-2 uses to infect cells, a receptor called ACE2.
“Doorway” to SARS-CoV-2 infection
There are several key reasons why we focused on ACE2 receptors. First, blocking this viral gateway does not require an optimally functioning immune system, so this method should be effective even in people who are immunocompromised.
And secondly, ACE2 receptors are produced by our own cells, so they are not affected by changes in the virus (i.e. new variants), which hopefully makes this method more robust as SARS-CoV-2 evolves.
So we were optimistic when we identified an existing drug that could modify ACE2 receptors. It is possible that this drug could be quickly redeveloped against COVID-19.
This research began with an accidental discovery. In the Sampaziotis lab at the University of Cambridge, we focus on liver regeneration and biliary tract disease, which are the main causes of liver transplants in children.
Bile is a digestive fluid produced by the liver and carried to the intestine through tubes called bile ducts. At the start of the pandemic, we studied the effects of bile on bile ducts using miniature dish-grown versions known as organoids.
We found that a bile-sensing molecule called FXR, which is abundant in the liver, controls the expression of many molecules in bile duct cells, including ACE2. When ACE2 was identified as the viral entry gate for SARS-CoV-2, we decided to investigate whether drugs targeting FXR could reduce ACE2 receptors and thus viral infection.
We found that ursodeoxycholic acid (UDCA), a clinically approved drug currently used for liver disease, had this effect on minibile ducts. We successfully repeated our experiments using miniature lungs and miniature intestines in the laboratory, as these organs are commonly affected by COVID-19.
We then verified these findings in hamsters to ensure that our laboratory results were valid in a living organism. To test whether these findings could be transferred to humans, we used a pair of donated human lungs that were not suitable for transplantation. We infected both lungs with SARS-CoV-2, but only one lung was treated with UDCA. We found that the lung that received the drug did not become infected, while the other lung did.
The next step was to test the effectiveness of UDCA in reducing ACE2 receptors in humans. We recruited eight healthy volunteers, administered UDCA, and then swabbed their noses. We observed a reduction of ACE2 in their nasal cells, which is the main point of entry of the virus into the body, suggesting that SARS-CoV-2 would have less opportunity to infect these cells.
Finally, because UDCA is widely used in clinical practice, we examined existing data to compare COVID outcomes among people taking UDCA for their liver conditions with outcomes among people not taking UDCA. We found that people taking UDCA were less likely to develop moderate, severe or critical COVID than those who did not receive the drug.
What could it all mean?
UDCA has been on the market for 30 years and is very safe with few side effects. In addition, the drug is off-patent, inexpensive, and easy to manufacture, store, and administer (taken in tablet form), making it suitable for use during outbreaks.
Although our results suggest that UDCA could protect against COVID, this study is not a clinical trial and only offers data to support this hypothesis. The next step will be to confirm our findings in a large randomized clinical trial. We do not support the use of UDCA for COVID until appropriate guidelines based on robust clinical evidence are available.
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In the future, UDCA would not replace current COVID treatments or highly effective vaccinations, but it might be able to expand our arsenal of weapons against the virus. It could offer an alternative strategy that is neither dependent on the immune system nor subject to immune evasion due to viral mutations.
Teresa Brevini, PhD candidate, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge and Fotios Sampaziotis, UKRI Future Leaders Fellow, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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