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United European Gastroenterology Journal ; 10(Supplement 8):210-211, 2022.
Article in English | EMBASE | ID: covidwho-2115468


Introduction: Vaccines revolutionised the management of COVID19. Nevertheless, they lack efficacy in high-risk or vulnerable groups (e.g., immunosuppressed patients), who may not mount an appropriate immune response. Monoclonal antibodies represent the gold-standard agents for such cases;but they are limited by availability, need for parenteral administration and the risk for viral escape because of spike protein mutations. Therefore, there is a pressing need for new prophylactic agents less prone to resistance.The viral receptor ACE2 represents an ideal target as it is essential for viral entry and transmission and because being a host protein it is not affected by viral mutations. However, the regulation of ACE2 remains elusive, due to the lack of appropriatein vitromodels. Cholangiocytes show one of the highest ACE2 expression levels in the body, representing an ideal platform for these studies. Here, we use cholangiocyte organoids as proof-of-principleto identify that the bile acid receptor FXR regulates ACE2 expression and SARS-CoV-2 infectionin vitro. We validate these findings in lung and gut organoids, animal models, human organs perfusedex situand patient cohorts. Aims & Methods: 1. Identify pathways controlling the transcriptional regulation of ACE2 2. Identify drugs modulating these pathways as novel prophylactic and therapeutic agents for COVID19. Organoids were propagated using established protocols. Marker expression was assessed using single-cell RNA sequencing, QPCR, and immunofluorescence. FXR binding on DNA was assessed with chromatin immunoprecipitation. SARS-CoV-2 was isolated from bronchoalveolar lavage of a COVID19 patient. Syrian golden hamsters were infected via direct inoculation and QPCR on oral swab, nasal turbinate and lung samples was used to measure SARS-CoV-2 infection. Human livers and lungs not used for transplantation were perfusedex-situusing normothermic perfusion. Nasopharyngeal swabs were used to measure ACE2 expression in nasal epithelial cells of healthy individuals taking UDCA at the standard therapeutic dose of 15 mg/kg/day. Patient registry data were compared using propensity score matching for sex, age, diabetes, NAFLD and Child- Turcotte-Pugh score. Result(s): We identified that FXR directly regulates ACE2 transcription in cholangiocyte organoids, while FXR inhibition with the approved drug ursodeoxycholic acid (UDCA), reduced ACE2 expression and SARS-CoV-2 infectionin vitro. We confirmed this mechanism in organoids from other COVID19-affected tissues, including the respiratory and intestinal systems. We validated our findingsin vivoin Syrian golden hamsters, showing that treatment with UDCA downregulates ACE2 and prevents SARS-CoV-2 infection. We confirmed that UDCA reduces ACE2 and SARS-CoV-2 infection in human lungs and livers perfusedex-situ. We performed a clinical study demonstrating that UDCA lowers ACE2 levels in the nasal epithelium of 6 healthy volunteers. Finally, we identified a correlation between UDCA and better clinical outcomes (hospitalisation, ICU admission and death) in COVID19 patients receiving UDCA for cholestatic diseases using the COVID-Hep and SECURELiver registry data. Conclusion(s): We identified FXR as a novel regulator of ACE2 expression. Using a bench-to-bedside approach combining in vitroand in vivomodels, exsituperfused human organs and clinical data we showed that FXR inhibition prevents or reduces SARS-CoV-2 infection and identified UDCA as an approved, cost-effective drug which could be repurposed for COVID19, paving the road for future clinical trials.

Journal of Heart and Lung Transplantation ; 40(4):S321-S321, 2021.
Article in English | Web of Science | ID: covidwho-1187436
The Journal of Heart and Lung Transplantation ; 40(4, Supplement):S321, 2021.
Article in English | ScienceDirect | ID: covidwho-1141819


Purpose The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic has caused widespread changes to healthcare practice. Demand on capacity, concerns for transplant recipients, including the risks of nosocomial infection, and the availability and safety of donors, lead to continuation of transplantation for only urgent and super-urgent, in-patient candidates, in the UK from March to May 2020. The aim of this study is to evaluate the impact of these practice changes on heart and lung donor utilisation during the pandemic period. Methods Data on all adult and paediatric heart and lung donors offered, and transplants performed, between 1 March and 30 September 2019 and 1 March and 30 September 2020 were obtained from the UK Transplant Registry. The early pandemic period is defined as 1 March to 31 May 2020. Ideal lung donors are defined as age <56 years and no smoking history. Results Lung transplant activity during the early pandemic period fell by 77% (13 transplants compared to 56 in 2019). Heart transplant activity fell by 10% (38 compared to 42 heart transplants in 2019). The number of donors, who donated at least 1 solid organ, fell by 51%. The lung donor utilisation rate during the early pandemic period was 11%, compared to 24% for the same period of 2019. The heart donor utilisation rate during the pandemic period was 35% compared to 26% during the same period of 2019. The proportion of ideal lung donors, from donors where lung(s) were offered, was 23% in 2020 compared to 24% in 2019. Following the early pandemic period (1 June to 30 September 2020), there has been an increase in the number of lung donors, lung transplant activity and utilisation, rising from 11% in March to May to 14% in June to September. This compares with a utilisation rate of 21% for the same period of 2019. Conclusion During the SARS-CoV-2 pandemic, changes to practice led to the continuation of heart transplantation, with minimal impact on activity, whilst lung transplant activity fell. The number of organ donors fell, while the ‘quality’ of potential lung donors remained unchanged. As the evidence base guiding clinical practice is evolving, along with improved donor testing, lung transplant activity is again increasing, however the utilisation of donors remains lower than in 2019. On-going analysis of activity is required to fully assess the impact of the SARS-CoV-2 pandemic on the UK lung transplant population.