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

Abstract

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

Case report: progressive familial intrahepatic cholestasis type 3 with compound heterozygous ABCB4 variants diagnosed 15 years after liver transplantation

“…Recently, two teams have successfully demonstrated stable ABCB4 gene expression and correction of PFIC3 phenotype in a murine model using adeno-associated virus serotype 8 (AAV8)-mediated gene therapy [19,20]. Other studies have shown that molecular chaperones may be of therapeutic value in PFIC syndromes, including PFIC3 [21][22][23][24][25].…”

Current Treatment Options for Cystic Fibrosis-Related Liver Disease

“…Finally, Ivacaftor has also shown therapeutic potential in an in vitro model of progressive familial intrahepatic cholestasis type 2 (PFIC2) caused by ABCB11 missense mutations affecting bile salt export pump (BSEP): Ivacaftor treatment increased the taurocholate transport activity of mutated BSEP by 1.7-fold, reaching 95% of BSEP function [ 60 ].…”

ABCB11 deficiency presenting as transient neonatal cholestasis: Correlation with genotypes and BSEP expression

“…To assess BSEP expression in liver thus may help predict prognosis and allow for improved personalized treatment. Also of help may be determinations of BSEP variant function in vitro 20 …”

“…Also of help may be determinations of BSEP variant function in vitro. 20 TNC may have been the first episode of BRIC in some of our patients, a possibility that in any individual can be excluded only with lifelong follow-up. Our study's brevity, with the shortest follow-up of only 1 year, thus constitutes a limitation in our work.…”