Unique experiments including ‘mini-organs’, animal research, donated human organs, volunteers and patients — ScienceDaily

In research involving a unique blend of “mini-organs”, donor organs, Cambridge scientists have identified a non-patent drug that can be reused to prevent COVID-19 and protect against future variants of the virus. animal studies and patients.

Research published today Natureshowed that an existing drug used to treat one type of liver disease can “lock” the door on the cell surface, a receptor known as ACE2, from which SARS-CoV-2 enters our cells. Because this drug targets host cells, not the virus, it should protect against future new variants of the virus as well as other coronaviruses that may emerge.

If confirmed in larger clinical trials, this could provide a vital drug to protect individuals for whom vaccines are ineffective or inaccessible, as well as individuals at high risk of infection.

Dr Fotios Sampaziotis from the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge and Addenbrooke Hospital led the research in collaboration with Professor Ludovic Vallier of the Berlin Health Institute in Charité.

“Vaccines protect us by boosting our immune system so that it can recognize and clear or at least weaken the virus,” said Dr Sampaziotis. “But vaccines don’t work for everyone, such as patients with compromised immune systems.” and not everyone has access to them. Moreover, the virus can evolve into new vaccine-resistant variants.

“We are interested in finding alternative ways to protect us from SARS-CoV-2 infection that is not immune-dependent and can complement vaccination. We have found a way to prevent its spread by closing the door to the virus.” It gets into our cells in the first place and protects us from infection.”

From mini organs and animals…

Dr Sampaziotis had previously worked with organoids — ‘mini-bile ducts’ — to study diseases of the bile ducts. Organoids are clusters of cells that can grow and multiply in culture, taking on a 3D structure with the same functions as the part of the organ under study.

Using these, the researchers found — quite luckily — that a molecule known as FXR, found in large quantities in these bile duct organoids, effectively opens and closes the viral ‘gate’ ACE2 by directly regulating it. They went on to show that ursodeoxycholic acid (UDCA), an off-patent drug used to treat a type of liver disease known as primary biliary cholangitis, ‘reverses’ FXR and closes the ACE2 gate.

In this new study, his team showed that they can use the same approach to shut down the ACE2 gate in the ‘mini-lungs’ and ‘mini-guts’, which represent the two main targets of SARS-CoV-2, and prevent the 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. Working with Professor Andrew Owen of the University of Liverpool for this, they have shown that the drug prevents infection in virus-exposed hamsters, which is used as the ‘gold standard’ model in preclinical testing against SARS-. CoV-2. More importantly, hamsters treated with UDCA were protected from the delta variant of the virus, which was new at the time and was partially resistant to current vaccines.

Professor Owen said: “While we need appropriately controlled randomized trials to confirm these findings, the data provide compelling evidence that UDCA may work as a drug to protect against COVID-19 and complement immunization programs in particularly vulnerable population groups. . targets the ACE2 receptor directly, we hope it may be more resistant to changes resulting from the evolution of the SARS-CoV-2 spike, which causes new variants to emerge rapidly.”

…to human organs…

Next, the researchers worked with Professor Andrew Fisher of Newcastle University and Professor Chris Watson of Addenbrooke hospital to see if their findings in hamsters hold true in human lungs exposed to the virus.

The team took a pair of donated lungs unsuitable for transplants, had them breathe outside the body with a ventilator, and used a pump to circulate blood-like fluid through them to keep the organs functioning while they could be examined. One lung was given the drug, but both were exposed to SARS-CoV-2. Of course, 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 on an entire human organ while being perfused. This could be important for organ transplants, given the risks of transmitting COVID-19 through transplanted organs,” said Professor Fisher. “This may open the possibility of treating organs with drugs to clear the virus before transplantation.”

… to people

Acting alongside human volunteers, the Cambridge team collaborated with Professor Ansgar Lohse of the Hamburg-Eppendorf University Medical Center in Germany.

Professor Lohse explained: “We recruited eight healthy volunteers to take the drug. When we sniffed these volunteers, we found lower levels of ACE2, suggesting that the virus would have less opportunity to enter the nasal cells and infect them.” main gateway for the virus.”

While it was not possible to conduct a full-scale clinical trial, the researchers did the second best thing: looking at data on COVID-19 outcomes from two independent patient cohorts, comparing individuals already taking UDCA for their liver condition. They found that patients taking UDCA versus patients not taking the drug were less likely to develop severe COVID-19 and be hospitalized.

A safe, affordable variable-resistant drug

Teresa Brevini, first author and PhD candidate from the University of Cambridge, said: “This unique study gave us the opportunity to truly do translational science, using a laboratory finding to directly address a clinical need.

“Using almost every approach at our fingertips, we’ve shown that an existing drug closes the door to the virus and can protect us from COVID-19. More importantly, because this drug works on our cells, it is unaffected by mutations in the virus and should be effective even if new variants emerge.”

Dr Sampaziotis said the drug could be a cost-effective and effective way to protect those for whom the COVID-19 vaccine is ineffective or inaccessible. “We have been using UDCA in the clinic for many years, so we know it is safe and very well tolerated, making it simple to administer to individuals at high risk of COVID-19.

“This tablet is low in cost, can be produced quickly in large quantities, and can be easily stored or shipped, making it easy to deploy quickly during epidemics – particularly against vaccine-resistant variants, where it may be the only line of protection while awaiting new vaccines will be developed. “We are optimistic that it can become an important weapon in our fight against -19.”

The research was funded largely by UK Research and Innovation, the European Society for the Study of the Liver, the NIHR Cambridge Biomedical Research Center and the Evelyn Trust.

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