BREAKING! Cambridge Study Finds That Cheap Generic Drug Ursodeoxycholic Acid Could Be Repurposed As A Prophylactic And Therapeutic Against COVID-19!

COVID-19 Drugs: A new breakthrough study led by researchers from Cambridge University-UK has found that the commonly available cheap generic drug used to treat a type of liver disease ie Ursodeoxycholic Acid (UDCA), could be repurposed to not only treat COVID-19 but also act as an effective prophylactic.


 
The drug is also not only effective against all existing SARS-CoV-2 variants but also against future emerging SARS-CoV-2 variants.
 
The study findings showed that Ursodeoxycholic Acid (UDCA), an existing drug used to treat a type of liver disease is able to ‘lock’ the doorway by which SARS-CoV-2 enters our cells, a receptor on the cell surface known as ACE2.
 
As the 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 might emerge.
 
Once confirmed in larger clinical trials, this breakthrough discovery could provide a vital drug for protecting those individuals for whom vaccines are ineffective or inaccessible as well as individuals at increased risk of infection.
 
Dr Fotios Sampaziotis, from the Wellcome-MRC Cambridge Stem Cell Institute at the University of Cambridge -UK and Addenbrooke’s Hospital-UK led the study in collaboration with Professor Dr Ludovic Vallier from the Berlin Institute of Health at Charité-Germany.
 
The study team previously discovered an important molecule that regulates ACE2 ‘binding capabilities.’
 
The study team used organoids which are clusters of cells that can grow and proliferate in culture, taking on a 3D structure that has the same functions as the part of the organ being studied, in this case being “mini bile-ducts.”
 
Utilizing these, the study team found rather that a molecule known as FXR or farnesoid X receptor, which is present in large amounts in these bile duct organoids, directly regulates the viral ‘doorway’ ACE2, effectively opening and closing it.
 
The researchers went on to discover that ursodeoxycholic acid (UDCA), an off-patent drug used to treat a form of liver disease known as primary biliary cholangitis, ‘turns down’ FXR and closes the ACE2 doorway.
 
In this new study, the research team showed that they could use the same approach to close the ACE2 doorway in organoids representing ‘mini-lungs’ and ‘mini-guts’ ie representing the two main targets of SARS-CoV-2 and prevent viral infection.
 
The study team next progressed to animal studies to validate vivo capabilities of ursodeoxycholic acid (UDCA).
 
The COVID-19 Drugs study team teamed up with Professor Dr Andrew Owen from the University of Liverpool-UK to show that the drug prevented infection in hamsters exposed to the virus, which are used as the ‘gold-standard’ mod el for pre-clinical testing of drugs against SARS-CoV-2.
 
Importantly, the hamsters treated with ursodeoxycholic acid or UDCA were protected from the delta variant of the virus, which was new at the time and was partially resistant to existing vaccines.
 
The study team next worked with Professor Dr Andrew Fisher from Newcastle University-UK and Professor Dr Chris Watson from Addenbrooke’s hospital-UK to see if their findings in hamsters held true in human lungs exposed to the SARS-CoV-2 virus.
 
The study team took a pair of donated lungs not suitable for transplantation, keeping them breathing outside the body with a ventilator and using a pump to circulate blood-like fluid through them to keep the organs functioning while they could be studied.
 
For the study, one lung was given the drug, but both were exposed to SARS-CoV-2.
 
Significantly, the lung that received the drug ursodeoxycholic acid (UDCA), did not become infected, while the other lung did.
 
Dr Sampaziotis told Thailand Medical News, “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 study team next moved to human clinical trials.
 
For this, the COVID-19 Drugs study team at Cambridge team collaborated with Professor Dr Ansgar Lohse from the University Medical Centre Hamburg-Eppendorf in Germany.
 
The combined study team recruited eight healthy volunteers to receive the drug. When the researchers swabbed the noses of these volunteers, they found lower levels of ACE2, suggesting that the SARS-COv-2 virus would have fewer opportunities to break into and infect their nasal cells which are the main gateway for the virus.
 
The study team also studied data on COVID-19 outcomes from two independent cohorts of patients, comparing those individuals who were already taking ursodeoxycholic acid (UDCA) for their liver conditions against patients not receiving the drug.
 
The researchers found that patients receiving ursodeoxycholic acid or UDCA were less likely to develop severe COVID-19 and be hospitalized.
 
The study team said that the drug could be an affordable and effective way of protecting those for whom the COVID-19 vaccine is ineffective or inaccessible.
 
Dr Sampaziotis said, “We have used ursodeoxycholic acid or UDCA in clinic 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. This tablet costs little, can be produced in large quantities fast and easily stored or shipped, which makes it easy to rapidly deploy during outbreaks – especially against vaccine-resistant variants, when it might be 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 study team is hoping to next find the necessary financial funding and support to conduct large randomized clinical trials.
 
The study team are the first to identify FXR ((farnesoid X receptor) as a direct regulator of angiotensin-converting enzyme-2 (ACE2) transcription among respiratory and gastrointestinal tissues impacted by COVID-19.
 
According to the study team, prevention of SARS-CoV-2 infection through the modulation of viral host receptors, such as ACE2, could represent a new chemoprophylactic approach for COVID-19.
 
To date however, the mechanisms controlling ACE2 expression remain elusive.
 
The study team identified farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems.
 
The COVID-19 Drugs study team then used the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signaling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters.
 
They demonstrated that UDCA-mediated ACE2 downregulation reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ.
 
The study team showed that ursodeoxycholic acid or UDCA reduces ACE2 expression in the nasal epithelium in humans and also showed a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection using retrospective registry data, and further confirmed these findings in an independent validation cohort of liver transplant recipients.
 
The study findings were published in the peer reviewed journal: Nature.
https://www.nature.com/articles/s41586-022-05594-0
 
The study team predicted that chenodeoxycholic acid (CDCA) might regulate ACE2 expression via FXR.
 
In order to test their theory, it was verified that FXR is expressed in vivo in gallbladder cholangiocytes and associated gallbladder cholangiocytes organoids (GCO) in vitro after activation by CDCA therapy.
 
To confirm whether FXR is required for CDCA-induced upregulation of ACE2, the team knocked down FXR among cholangiocyte organoids with short hairpin ribonucleic acid (shRNA), which blocked CDCA-induced upregulation of small heterodimer partner (SHP) and ACE2.
 
Next, to determine if FXR could interact with the ACE2 gene and possibly regulate its transcriptional activity, the study team assessed the ACE2 promoter region and noted the existence of an FXR-responsive element.
 
The COVID-19 Drugs study team examined in vitro whether FXR-mediated downregulation of ACE2 could diminish susceptibility to COVID-19.
 
The study team also subjected airway, gallbladder cholangiocyte, and intestine organoids to physiological amounts of CDCA to imitate the base level of FXR activation noted in vivo. These tissues were then infected with SARS-CoV-2, collected from a patient's nasopharyngeal swab with or without the presence of z-guggulsterone (ZGG) or ursodeoxycholic acid (UDCA).
 
Subsequently, the research team determined if the observed decrease in SARS-CoV-2 infection was a direct consequence of FXR-mediated ACE-2 downregulation.
 
In order to assess whether ACE2 regulation is the sole mechanism through which ZGG and UDCA inhibit SARS-CoV-2 infection, HEK293T cells were modified to over-express ACE2 irrespective of FXR with ZGG or UDCA followed by SARS-CoV-2 infection. The potential effects of UDCA treatment on COVID-19 patient outcomes were also tested by querying the COVID-Hep/SECURELiver registries. These registries provide information on patients with chronic liver disease who also tested COVID-19-positive and those with cholestatic liver diseases who received ursodeoxycholic acid (UDCA).
 
The COVID-19 Drugs study team using chromatin immunoprecipitation, confirmed that active FXR could bind directly to the ACE2 promoter. Significantly, site-specific mutation of the IR-1 region decreased the luciferase signal, revealing the FXR binding site specificity to the ACE2 promoter.
 
Importantly, in contrast, inhibition of FXR signaling with the FXR antagonist ZGG or ursodeoxycholic acid (UDCA) decreased FXR activity, as indicated by lowered levels of SHP, reduced FXR levels on ACE2 promoter, and ACE-2 downregulation at the protein and transcript. Collectively, the findings indicate that FXR directly regulates ACE2 expression in cholangiocytes.
 
Significantly, the study also noted that inhibiting FXR signaling with U.S, FDA approved drug ursodeoxycholic acid (UDCA) decreases ACE2 expression in many cell types.
 
Ursodeoxycholic acid (UDCA) mediated inhibition of FXR signaling lowered SARS-CoV-2 infection in all three types of organoids, demonstrating that knocking down FXR with shRNAs reduces ACE2 expression and suppresses viral infection among cholangiocyte organoids regardless of the presence of UDCA/ZGG or CDCA. Thus, after knockdown, neither UDCA nor ZGG affected viral infection.Without ACE2 regulation, neither UDCA nor ZGG affected viral replication.
 
The research findings demonstrate that Ursodeoxycholic acid (UDCA) decrease susceptibility to COVID-19 in several cell types in vitro by regulating ACE2 via FXR.
 
Utilizing multivariable logistic regression, the study team noted that Ursodeoxycholic acid (UDCA) exposure was related to a 46% decreased risk of contracting COVID-19. The connection was detected across the COVID-19 spectrum concerning symptomatic disease.
 
Future large randomized clinical trials should validate the effectiveness of Ursodeoxycholic acid (UDCA) as a COVID-19 prophylactic and therapeutic agent.
 
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