FXR INHIBITION AS A NEW STRATEGY AGAINST COVID19 T Brevini1, M Maes2, GJ Webb3, CD Fuchs4, G Buescher5

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.

Impact of restrictions due to covid-19 on a quality assured screening colonoscopy program

Aims On February 25 , the first patient was diagnosed with COVID-19 in Austria. On March 16 (week 12) Austriangovernment imposed restrictions and subsequently the Austrian Medical Association has recommended to minimizescreening examinations in compliance with government restrictions. Aim Aim was to evaluate the impact of this recommendation on the number of weekly performed colonoscopies, detection of non-advanced adenomas, advanced adenomas (AA) and colorectal cancer (CRC) and to calculate how many undetectedadenomas could develop into CRC. Methods We analyzed number of colonoscopies and pathological findings within a quality assured national colorectal cancerscreening program before the COVID-19 pandemic (January 1 2019 - July 5 2019, Period 1) and compared those ratesto months with limited access to colonoscopy (January 1 2020 and July 5 2020, Period 2) with a two-tailed T-test, aWilcoxon-rank-test and a chi-square test. Results 23.700 colonoscopies were performed in Period 1, and 15.569 in Period 2. The mean rate of colonoscopies perweek in Period 1 was significantly higher than in Period 2 (877,78 [SD=190,44] versus 576,63 [SD=350,58], p = 0,003).4.655 non-advanced adenomas were detected in Period 1 versus 3.221 in Period 2 (p = 0,012). In total 1.863 AAs and 170CRCs were detected in Period 1 versus 1.166 AAs and 91 CRCs in Period 2. These rates did not differ significantly (p = 0,177, and p = 0,131). Conclusions During the COVID-10 the number of performed colonoscopies per endoscopist was significantly lowercompared to the years before but there was no difference in the detection of CRCs and AAs.