Unique Experiments Using “Mini-Organs”, Animal Experiments, Donated Human Organs, Volunteers and Patients – ScienceDaily

Cambridge scientists have identified an off-patent drug that can be repurposed to prevent COVID-19 – and may be able to protect against future variants of the virus – in research involving a unique mix of ‘mini-organs’ Donor organs, animal studies and patients.

The study published today in Nature, showed that an existing drug used to treat a type of liver disease is able to “shut the door” by which SARS-CoV-2 enters our cells, a receptor on the cell surface known as ACE2. Because this drug targets the host cells and 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 represent a vital drug to protect those for whom vaccines are ineffective or inaccessible, and those at increased risk of infection.

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

dr Sampaziotis said: “Vaccines protect us by boosting our immune system so it can recognize and eliminate, or at least weaken, the virus. But vaccines don’t work for everyone — for example, patients with a weakened immune system — and not everyone has access to them. In addition, the virus can mutate into new vaccine-resistant variants.

“We are interested in finding alternative ways to protect ourselves from SARS-CoV-2 infection that are not dependent on the immune system and could complement vaccination. We have discovered a way to close the door on the virus and prevent it from spreading in the first place, entering our cells and protecting 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 and adopt a 3D structure that has the same functions as the part of the organ under study.

Using these, the researchers found – rather coincidentally – that a molecule called FXR, present in large amounts in these organoids of the bile duct, directly regulates the viral “gate” ACE2, effectively opening and closing it. They went on to show that ursodeoxycholic acid (UDCA), a patent-free drug used to treat a form of liver disease known as primary biliary cholangitis, “turns off” FXR and closes the ACE2 door.

In this new study, his team showed that they could use the same approach to shut the ACE2 door in “mini-lungs” and “mini-guts” — which are the two main targets of SARS-CoV-2 — and viruses to prevent infection.

The next step was to show that the drug could prevent infections not only in cells grown in the lab, but also in living organisms. To do this, they have teamed up with Professor Andrew Owen of the University of Liverpool to show that the drug prevents infections in hamsters exposed to the virus, which is being used as the ‘gold standard’ model for pre-clinical testing of drugs against SARS. CoV-2. Importantly, the hamsters treated with UDCA were protected from the then-new Delta variant of the virus, which was partially resistant to existing vaccines.

Professor Owen said: “Although we will need properly controlled randomized trials to confirm these results, the data provide compelling evidence that UDCA could act as a drug to protect against COVID-19 and complement immunization programmes, particularly in vulnerable populations directly targeting the disease.” ACE2 receptor, we hope that it will be more resilient to changes resulting from the evolution of the SARS-CoV-2 spike leading to the rapid emergence of new variants.”

… to human organs …

Next, the researchers worked with Professor Andrew Fisher from Newcastle University and Professor Chris Watson from Addenbrooke Hospital to see if their findings applied to hamsters in human lungs exposed to the virus.

The team removed a pair of donated lungs that weren’t suitable for transplant, made them breathe outside the body on a ventilator, and used a pump to circulate blood-like fluid through them to keep the organs functional while they’re examined could. One lung was given the drug, but both were exposed to SARS-CoV-2. In fact, the lung that received the drug did not become infected, while the other lung did.

Professor Fisher said: “This is one of the first studies to test the effects of a drug in an entire human organ while it is being perfused. This could prove important for organ transplantation – given the risks of transmitting COVID-19 through transplanted organs, it could open up the possibility of treating organs with drugs to eliminate the virus before transplantation.”

… to people

In addition to human volunteers, the Cambridge team worked with Professor Ansgar Lohse from the University Hospital Hamburg-Eppendorf in Germany.

Professor Lohse explained: “We recruited eight healthy volunteers to receive the drug. When we swabbed the noses of these volunteers, we found lower levels of ACE2, suggesting the virus would have fewer opportunities to enter and infect their nasal cells — the main entry points for the virus.”

Although it was not possible to conduct a full-scale clinical trial, the researchers did the next best thing: they examined data on COVID-19 outcomes from two independent cohorts of patients and compared those who were already taking UDCA for their liver disease versus those who were taking it drug not received. They found that patients who received UDCA were less likely to develop severe COVID-19 and be hospitalized.

A safe, affordable variant-safe drug

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

“With almost every approach at our disposal, we have shown that an existing drug can close the door on the virus and protect us from COVID-19. Importantly, since this drug works on our cells, it is not affected by mutations in the virus and should be effective even if new variants emerge.”

dr Sampaziotis said the drug could be an affordable 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 straightforward to administer to those at high risk of COVID-19.

“This tablet is inexpensive, quick and easy to mass-produce and store or ship, facilitating rapid deployment during outbreaks – particularly against vaccine-resistant variants when it may provide the only line of protection while waiting for new vaccines to be developed. We are optimistic that this drug could become an important weapon in our fight against COVID-19.”

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

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