Functional rescue of an ABCB11 mutant by ivacaftor: A new targeted pharmacotherapy approach in bile salt export pump deficiency.

Autor: Mareux E; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France., Lapalus M; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France., Amzal R; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France., Almes M; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France.; Paediatric Hepatology & Paediatric Liver Transplant Department, Reference Center for Rare Paediatric Liver Diseases, FILFOIE, ERN RARE LIVER, Assistance Publique-Hôpitaux de Paris, Faculty of Medicine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France., Aït-Slimane T; Inserm, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France., Delaunay JL; Inserm, Centre de Recherche Saint-Antoine (CRSA), UMR_S 938, Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Université, Paris, France., Adnot P; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France., Collado-Hilly M; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France., Davit-Spraul A; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France.; CHU Bicêtre, Biochemistry Unit, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France., Falguières T; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France., Callebaut I; Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie de Physique des Matériaux et de Cosmochimie, IMPMC, Sorbonne Université, Paris, France., Gonzales E; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France.; Paediatric Hepatology & Paediatric Liver Transplant Department, Reference Center for Rare Paediatric Liver Diseases, FILFOIE, ERN RARE LIVER, Assistance Publique-Hôpitaux de Paris, Faculty of Medicine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France., Jacquemin E; Inserm, Physiopathogénèse et traitement des maladies du foie, UMR_S 1193, Hepatinov, Université Paris-Saclay, Orsay, France.; Paediatric Hepatology & Paediatric Liver Transplant Department, Reference Center for Rare Paediatric Liver Diseases, FILFOIE, ERN RARE LIVER, Assistance Publique-Hôpitaux de Paris, Faculty of Medicine Paris-Saclay, CHU Bicêtre, Le Kremlin-Bicêtre, France.
Jazyk: angličtina
Zdroj: Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2020 Aug; Vol. 40 (8), pp. 1917-1925. Date of Electronic Publication: 2020 Jun 08.
DOI: 10.1111/liv.14518
Abstrakt: Background & Aim: The canalicular bile salt export pump (BSEP/ABCB11) of hepatocytes is the main adenosine triphosphate (ATP)-binding cassette (ABC) transporter responsible for bile acid secretion. Mutations in ABCB11 cause several cholestatic diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) often lethal in absence of liver transplantation. We investigated in vitro the effect and potential rescue of a BSEP mutation by ivacaftor, a clinically approved cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7) potentiator.
Methods: The p.T463I mutation, identified in a PFIC2 patient and located in a highly conserved ABC transporter motif, was studied by 3D structure modelling. The mutation was reproduced in a plasmid encoding a rat Bsep-green fluorescent protein. After transfection, mutant expression was studied in Can 10 cells. Taurocholate transport activity and ivacaftor effect were studied in Madin-Darby canine kidney (MDCK) clones co-expressing the rat sodium-taurocholate co-transporting polypeptide (Ntcp/Slc10A1).
Results: As the wild-type protein, Bsep T463I was normally targeted to the canalicular membrane of Can 10 cells. As predicted by 3D structure modelling, taurocholate transport activity was dramatically low in MDCK clones expressing Bsep T463I . Ivacaftor treatment increased by 1.7-fold taurocholate transport activity of Bsep T463I (P < .0001), reaching 95% of Bsep wt activity. These data suggest that the p.T463I mutation impairs ATP-binding, resulting in Bsep dysfunction that can be rescued by ivacaftor.
Conclusion: These results provide experimental evidence of ivacaftor therapeutic potential for selected patients with PFIC2 caused by ABCB11 missense mutations affecting BSEP function. This could represent a significant step forward for the care of patients with BSEP deficiency.
(© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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