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 study findings were published in the peer reviewed journal: Nature.
Considered collectively, our findings demonstrate that FXR participates in the regulation of ACE2 expression in multiple tissues involved in SARS-CoV-2 replication. Suppression of FXR activity, using the clinically approved drug UDCA, downregulates ACE2 expression and reduces SARS-CoV-2 infection in vitro, in vivo and ex vivo.
Furthermore, our clinical observations indicate that UDCA reduces ACE2 levels in the nasal epithelium of healthy individuals and suggest a potential correlation between UDCA and positive clinical outcomes in COVID-19 patients.
The finding that FXR regulates ACE2 is novel but not entirely surprising. The functions of ACE2 as a molecular chaperone for the amino acids transporter SLC6A19 and as a peptidase justify its presence in the GI tract and suggest a potential role in digestion. Accordingly, the upregulation in ACE2 expression by FXR, which is activated by bile, a digestive fluid, may reflect a mechanism to increase peptidase levels and amino acids absorption during digestion.
Furthermore, in addition to its role in the GI system, FXR is expressed in multiple organs, including the lungs20,21, with a broad variety of functions, ranging from bile acid22 and lipid metabolism36, to glucose homeostasis 37, fibrosis 38 and inflammation 39. Importantly, its natural ligands, such as bile acids and hormones40 (e.g., androgens) are present in the systemic circulation22; and it is the therapeutic target of several approved drugs 17. This broad expression and function explain how FXR could regulate ACE2 in multiple tissues beyond the biliary tree.
Our results illustrate the potential of ACE2 modulation as a novel host-directed treatment which might be efficacious as primary and secondary prophylaxis in COVID-19. These
findings are in keeping with existing studies illustrating the benefits of targeting the virus-host interaction for SARS-CoV-2 at the level of ACE21 or the spike protein 7. Indeed, large Mendelian randomization analyses in over 7,554 patients hospitalised with COVID-19 and more than 1 million controls demonstrated that higher ACE2 levels strongly correlated with increased risk of COVID-19 hospitalisation, identifying ACE2 as a logical candidate for drug development in COVID191.
Additionally, the extensive clinical literature supporting Ronapreve and Evusheld, both dual combinations of monoclonal antibodies against the SARS-CoV-2 spike protein, demonstrates the utility of inhibiting the viral spike protein-ACE2 interaction for prophylaxis and treatment in COVID19 for susceptible pre-Omicron variants 41,42.
However, targeting the viral spike protein with monoclonal antibodies is limited by diversity and evolution of the viral spike sequences, rendering many of these agents ineffective against new SARS-CoV-2 variants 7.
Conversely, targeting ACE2 is advantageous for multiple reasons. ACE2 modulation is a host-directed treatment, which does not target the virus. Such mechanisms may present a higher barrier to emergence of resistance although this has yet to be empirically demonstrated.
Furthermore, since ACE2 is a critical mechanism for cell entry, the approach maybe more resilient as variants continue to emerge 43. Finally, ACE2 is a common receptor for multiple coronaviruses, such as SARS- CoV and HCoV-NL63. Confirmation of the efficacy of this strategy may therefore provide a quickly deployable intervention in the event of future coronavirus outbreaks.
Taken collectively with our own observations on the effects of ACE2 modulation for SARS-CoV-2 infection, these points illustrate that ACE2 modulators warrant consideration as priority candidates for clinical evaluation in COVID-19 trials1.
Our finding that FXR signalling suppression through UDCA or ZGG reduces ACE2 expression, and limits SARS-CoV-2 infection, identifies a new potential clinical application for FXR inhibitors, but also raises some points for consideration.
First, FXR activation decreases inflammation by modulating NFkB in multiple organs 44, including lungs 21, liver 17 and intestine 17.
Conversely, UDCA has been shown to reduce inflammation in multiple tissues, including lung, in an FXR-independent fashion 45. Given the complex interplay between FXR, UDCA and inflammation 46, the balance of benefits for FXR activation in terms of SARS-CoV-2 infection and inflammation should be carefully considered.
It is possible that FXR suppressors, beyond UDCA, which lack anti-inflammatory effects would be better suited for prophylaxis or early intervention and not indicated for severe disease with ongoing tissue inflammation47. Second, our study suggests that FXR activators used in clinical practice, such as obeticholic acid (OCA) may increase the risk of developing COVID-19 by upregulating ACE2 in healthy individuals.
Conversely, in liver patients OCA may paradoxically prevent COVID-19 by reducing disease severity and ameliorating cholestasis, resulting in a net reduction of FXR activity. Therefore, further studies are needed to elucidate these points. Our results identify UDCA as a particularly advantageous modulator of ACE2 levels, for use in COVID-19. We demonstrated that UDCA reduces SARS-CoV-2 infection in vitro, in vivo and ex vivo; and lowers ACE2 expression in the nasal epithelium of healthy volunteers.
Although our animal data do not exclude that UDCA delays SARS-CoV-2 transmission beyond the duration of our experiments; our patient data illustrate that this does not change the net effect of reducing disease severity, which make it particularly attractive for investigation as pharmacological prophylaxis against SARS-CoV-2 infection.
Compared to other agents, such as vaccines and monoclonals, it is easy to administer orally, easily stored, affordable and accessible to health systems world-wide for large scale production, as it is off patent. In addition, UDCA is well-tolerated, has limited drug- drug interactions, and a favourable safety profile enabling it to be administered for long periods of time. Of note, UDCA is already administered long-term for different clinical indications to vulnerable groups that would benefit from chemoprophylaxis, such as bone marrow and liver transplant patients,
for prevention of veno-occlusive disease48 and treatment of cholangiopathy26 respectively. It has excellent tolerability and minimal side effects in these patient groups 26,48 demonstrating the potential feasibility of using UDCA as pharmacological prophylaxis against COVID19 in vulnerable groups. Nevertheless, our study is not a clinical trial and therefore we cannot exclude the potential for confounding and selection biases.
Consequently, it will be imperative to validate these results in prospective double blinded clinical trials and fully assess the impact of this drug on ACE2 levels and susceptibility to SARS-CoV-2 infection. For the absence of doubt, the authors do not support use of UDCA for COVID19 until appropriate policy informed by robust clinical evidence is available. The authors also do not condone the use of UDCA as a substitute for highly effective vaccinations in patients for which they are indicated.
Finally, we demonstrated that UDCA could reduce ACE2 levels and SARS-CoV-2 infection in machine perfused organs. This is one of the first studies testing the effect of a drug in a whole human organ perfused ex situ. This finding could prove important for organ transplantation, especially given concerns about peri-operative viral transmission 49. Furthermore, although more data are required to definitively establish this approach, our work sets the stage for future studies using machine-perfused organs for pharmacological studies.
In conclusion, these results validate CDCA-treated cholangiocytes organoids as a novel platform for disease modelling and drug testing against SARS-CoV-2 infection; identify FXR as a new therapeutic target in the management of COVID-19 and open up new avenues for the modulation of ACE2 through FXR for prevention of SARS-CoV-2 infection as well as other viruses using ACE2 for cell entry.