Drug for liver disease could protect against infection with SARS-CoV-2

… and help COVID-19 patients.

Scientists from the Berlin Institute of Health at Charité (BIH), together with colleagues from Germany and the UK, have found that a commonly used liver drug also affects infection with the SARS-CoV-2 coronavirus. It causes the number of ACE-2 receptors on the cells to decrease, which makes it harder for the virus to enter the cells. The researchers were able to demonstrate this in various cultured organoids in the laboratory, as well as in living animals and in humans who had taken the drug. The scientists have now published their results in the journal Nature.

Ludovic Vallier is actually interested in the liver. The holder of an Einstein strategic Professorship for Stem Cells in Regenerative Therapies at BIH and Max-Planck-Fellow at Max-Planck-Institute for molecular genetics grows mini livers, so-called organoids, in order to research how diseases of the liver develop and how they can be treated or prevented. As a long-term goal, he would also like to use liver organoids for cell based therapies for patients with liver failure.

When the SARS-CoV-2 coronavirus emerged in 2020, Vallier’s team, especially Fotios Sampaziotis and Teresa Brevini, who were working with Dr. Ludovic Vallier during his time at the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge, also turned their attention to researching this new threat. “We were surprised when we discovered that liver cells carry a lot of ACE-2 molecules on their surface, which is the receptor for this strain of coronavirus. This is because the liver was not previously known to be particularly affected by infection or by COVID19 disease.”

Bile acid increases the number of ACE-2 receptors

The scientists then investigated how the amount of ACE-2 molecules on the liver cells is controlled. They discovered an interesting mechanism: particularly high concentrations of the ACE-2 receptor – the highest in the human body – were found on the epithelial cells lining the bile ducts and gallbladder. These cells can be easily grown in vitro as organoids. However, they lose the expression of ACE-2 if they are not regularly flushed with a bile acid.

“When we omitted the bile acid from the culture medium, the cells lost the ACE-2 receptor. We were thus able to identify bile acid as a regulator of the ACE-2 receptor”, reports Vallier. The mechanism behind this is even more complicated: bile acid activates the receptor FXR, which in turn stimulates the production of ACE-2. Without bile acid, no FXR; without FXR, no ACE-2.

Suppression of bile acids lowers ACE-2 receptors also in lungs and intestines

“Now, of course, we wanted to know whether this correlation also existed in the tissues that are the actual target of the coronavirus, i.e., in the lung and intestine. And indeed, we also found FXR in organoids generated from lung or intestinal cells, and there, too, treatment with bile acids caused an increase in FXR and then in ACE-2”, Vallier explains.

The exciting question now was whether the process could also be reversed: could the amount of ACE-2 receptors also be lowered via this route? Vallier says: “We were lucky that there are already drugs on the market that lower the concentration of bile acids in the context of liver diseases. We added these substances to the different organoids from liver, lung and intestine, and indeed, as a result, the concentration of ACE-2 receptors decreased.”

Principle also works in organoids and animals…

In a next step, the scientists infected organoids of liver, lung or intestine with SARS-CoV-2 viruses, which they had obtained from nasal swabs of infected patients. Some of the organoids had been pre-treated with the drug, while others had not. And indeed, the drug caused the infection rate to drop sharply.

Mice and hamsters given the drug also showed significantly fewer ACE-2 receptors in their nasal, lung, liver and intestinal epithelial cells. And indeed, the drug protected hamsters from infection with the virus: of six untreated hamsters, all contracted the virus from another infected animal, became ill and lost weight. Of nine animals pretreated with the drug, only three became infected and also fell ill less severely. “We were thus able to show that the drug was indeed effective in preventing infection,” says Ludovic Vallier. “However, of course, we wanted to show this in humans, not hamsters.”

…and finally in humans

The scientists* next studied donated human lungs that were perfused and ventilated outside the body. The two lungs were perfused separately in order to be able to check the effect of the drug on one and the same organ. Consequently, they perfused one lung with a treatment-standard concentration of the drug and the other with placebo. The ACE-2 level in the two lungs, which was still the same at the beginning of the experiment, then changed: it dropped sharply in the treated part. When the researchers subsequently infected the two lungs with SARS-CoV-2, it was shown that pretreatment with the drug actually significantly impeded the infection.

In a subsequent test, eight volunteers received the drug at the usual dosage for six days. “After that, we found in their nasal swabs that the concentration of the ACE-2 receptor on their nasal epithelial cells had significantly reduced. Serum from patients with congenital liver disease who had been taking the drug for a long time also showed lower ACE-2 concentrations than patients not taking the drug. Finally, data on patients with liver disease who also had COVID-19 also found that patients treated with the drug had significantly milder disease courses, required less intensive care and died less frequently.

Inexpensive and with few side effects

A drug directed against the body’s own molecule would have several advantages over a drug directed against the virus. Unlike the virus, the body’s own ACE receptor does not change, so there is less risk of resistance. Because it has been used for many years, it is known to be well tolerated in the long term. It is off-patent and therefore available at low cost.

“We are of course excited by these results,” Ludovic Vallier reports, “because we believe we have found a way to both prevent COVID-19 and treat it in the early stages of infection. Of course, we know full well that we need to conduct proper clinical trials to verify this hope. But if successful, we would have in our hands a low-cost, low-side-effect drug that is quickly and globally available, and with which we could well help many people. And that is our goal!”

Reference: Teresa Brevini, Mailis Maes, Gwilym J. Webb, …..Ludovic Vallier and Fotios Sampaziotis; FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2. Nature (2022). https://doi.org/10.1038/s41586-022-05594-0

About the Berlin Institute of Health at Charité (BIH)
The mission of the Berlin Institute of Health at Charité (BIH) is medical translation: transferring biomedical research findings into novel approaches to personalized prediction, prevention, diagnostics and therapies and, conversely, using clinical observations to develop new research ideas. The aim is to deliver relevant medical benefits to patients and the population at large. As the translational research unit within Charité, the BIH is also committed to establishing a comprehensive translational ecosystem – one that places emphasis on a system-wide understanding of health and disease and that promotes change in the biomedical translational research culture. The BIH was founded in 2013 and is funded 90 percent by the Federal Ministry of Education and Research (BMBF) and 10 percent by the State of Berlin. The founding institutions, Charité – Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), were independent member entities within the BIH until 2020. Since 2021 the BIH has been integrated into Charité as its so-called third pillar. The MDC is now the Privileged Partner of the BIH.

Contact
Dr. Stefanie Seltmann
Head of Communications
Berlin Institute of Health at Charité (BIH)
stefanie.seltmann@bih-charite.de
+49 (0)30 450 543019
www.bihealth.org

About the Einstein Foundation Berlin
The Einstein Foundation Berlin is an independent, not-for-profit, science-led organization established as a foundation under civil law in 2009. Since then, its task has been to promote international cutting-edge science and research across disciplines and institutions in and for Berlin. To date, it has funded more than 200 researchers, including three Nobel laureates, 70 projects, and seven Einstein Centers. The Einstein Foundation Berlin receives funding from the State of Berlin and from private donors such as the Damp Stiftung. The former majority owner of the Klinikgruppe Damp, Dr. Walter Wübben, established the Damp Stiftung to fund medical research and teaching as well as social projects.

Contact
Christian Martin
Head of Communications
Einstein Foundation Berlin
+49(0)30 20370–248
cm@einsteinfoundation.de
www.einsteinfoundation.de

Originalpublikation:

10.1038/s41586-022-05594-0

Weitere Informationen:

https://www.bihealth.org/en/notices/drug-for-liver-disease-could-protect-against…