Author: De Meyer, Amse ; Pavio, Nicole ; Fouillé, Roxanne ; Verrier, Eloi R ; Barnault, Romain ; Meuleman, Philip ; Pons, Caroline ; Diaz, Olivier ; Darteil, Raphaël ; Salvetti, Anna ; Lucifora, Julie ; Rivoire, Michel ; Michelet, Maud ; Wedemeyer, Heiner ; Durantel, David ; Passot, Guillaume ; Steinmann, Eike ; Doceul, Virginie ; Verhoye, Lieven

Background & AimsThe liver, and more precisely hepatocytes, can be infected by several hepatotropic viruses, including HBV, HDV, HCV and HEV, with chronic infection leading to end-stage liver diseases. Since no in vitro model allowing multi-infections with the four viruses is reported, limited data are available on their interplay as well as on the potential cross-reactivity of antivirals in multi-infection cases. The aim of our study was to set up such a model.MethodsHuH7.5-NTCP cells were cultured with 2% DMSO (dimethyl sulfoxide) for 1 week to allow partial differentiation into hepatocytes (dHuH7.5-NTCP) before infection with the different viruses and treatment with known antiviral molecules.ResultsWe observed increased expression of liver specific transcripts and production of ApoB containing VLDL in dHuH7.5-NTCP cells and replication of HBV, HDV, HCV and HEV for at least 4 weeks after mono or multiple infections. We recapitulated the known antiviral effect of sofosbuvir on HCV and HEV (>90% reduction in the levels of intracellular viral RNAs, p <0.0005) and of IFN-α on HCV, HEV and HDV (80% reduction in the levels of intracellular viral RNAs, p <0.0005). Besides its already described antiviral effect on HBV and HDV, we observed that GW4064, a farnesoid X receptor (FXR) agonist, also strongly inhibited HEV replication (85 to 95% reduction in the levels of intracellular HEV RNAs, p <0.0005). Using HEV-infected HuHep mice, we confirmed the antiviral effect of vonafexor, an FXR agonist, that is currently being tested clinically against HBV/HDV.ConclusionsWe set-up the first in vitro model allowing multi-infections with hepatitis viruses that can be used for broad drug screening and highlighted FXR ligands as potential broad-acting antivirals.Impact and implicationsHepatitis virus infections caused by HBV, HCV, HDV, and HEV represent a global health threat. Treatment options remain limited, notably due to the lack of knowledge about molecular virus-host interactions. Moreover, the interplay between these four viruses in the context of co-infections remains unknown. In this study, we report the first in vitro system that allows for mono and multi-infections with these four viruses and characterize the broad antiviral activity of farnesoid X receptor agonists, paving the way for the development of new strategies for viral cure.

01 Apr 2025·European Journal of Internal Medicine

A physico-chemical explanation for the litho-protective effects of obeticholic acid in low phospholipid-associated cholelithiasis

Review

Author: Moschetta, Antonio ; van Berge Henegouwen, Gerard P ; Portincasa, Piero ; van Erpecum, Karel J

Patients with low phospholipid-associated cholelithiasis may suffer from recurrent biliary symptoms and complications despite cholecystectomy and ursodeoxycholic acid therapy. Recently, beneficial clinical effects of treatment with the potent Farnesoid X receptor (i.e. bile salt receptor) agonist obeticholic acid in combination with ursodeoxycholic acid were reported in this patient group. In contrast, other studies reported more gallstone-related events and increased cholesterol saturation indices in gallbladder biles during obeticholic acid monotherapy. We here provide an in-depth review on solubilization and crystallization of cholesterol in bile, including all relevant physico-chemical aspects of cholesterol gallstone pathogenesis. We offer an explanation that reconciles seemingly contradictory data in previous publications. We propose that, due to the well-known inhibition of intra-hepatic bile salt synthesis from cholesterol by Farnesoid X receptor stimulation, biliary bile salt concentrations decrease during obeticholic acid therapy. As a result, biliary cholesterol solubilization shifts from mixed micelles into cholesterol-phospholipid vesicles, with inhibited cholesterol crystallization despite increased cholesterol saturation index (the latter takes only micellar cholesterol solubilization into account). We suggest that obeticholic acid has a lithoprotective effect, provided that increased bile salt hydrophobicity from obeticholic acid (a quite hydrophobic bile salt that is secreted into bile) is prevented by concomitant ursodeoxycholic acid therapy. We also suggest future directions for research into the role of obeticholic acid and other Farnesoid X receptor agonists to improve the prospects of low phospholipid-associated cholelithiasis patients and other gallstone patients with persisting biliary problems after cholecystectomy. In conclusion, obeticholic acid may enhance lithoprotective effects of ursodeoxycholic acid.

01 Feb 2025·Clinics and Research in Hepatology and Gastroenterology

Assessing the efficacy of farnesoid X receptor agonists in the management of metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis

Review

Author: Nagar, Tripti ; Ahmed, Ali ; Jamil, Adeena ; Alzaher, Mojtaba Hussain ; Kumar, Jai ; Kumar, Sarwan ; Mohsin, Sana ; Hasan, Misha ; Lavu, Vamsi Krishna

BACKGROUND AND AIMSSeveral randomized clinical trials have been conducted assessing the potential efficacy of Farnesoid X receptor (FXR) agonists in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). A comprehensive review and analysis were needed to evaluate the findings of these trials. Hence, this systematic review and meta-analysis aim to study the association between FXR agonists and hepatic outcomes in patients with MASLD.METHODSSystematic review and meta-analysis evaluating the efficacy of FXR agonists in 1,227 patients assigned to the FXR intervention group compared to 650 patients in the placebo group. Changes in liver enzymes and hepatic steatosis assessed by MRI-PDFF were evaluated.RESULTSFXR agonist use was associated with a significant reduction in levels of AST, (WMD= -4.51, 95% CI=[-8.39,-0.63], P=0.02); ALT (WMD= -13.02, 95% CI=[-17.85,-8.19], P<0.00001); GGT (WMD= -32.20, 95% CI=[-38.63,-25.98], P<0.00001); MRI-PDFF, (SMD= -1.14, 95% CI=[-1.92,-0.35], P=0.005). FXR agonists did not significantly affect ALP levels, (WMD= 25.04, 95% CI=[19.22,30.87], P<0.00001] CONCLUSION: Results show promising evidence supporting the efficacy of FXR agonists in reducing hepatic steatosis and biomarkers of hepatic injury such as ALT, AST, and GGT.

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Indication	Highest Phase	Country/Location	Organization	Date
Nonalcoholic Steatohepatitis	Preclinical	Sweden	Inorbit Therapeutics AB	-

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