title: Successful mutation-specific chaperone therapy with 4-phenylbutyrate in a child with progressive familial intrahepatic cholestasis type 2.
abstract: OBJECTIVE
  Progressive familial intrahepatic cholestasis type 2 (PFIC2) is due to mutations in ABCB11 encoding the canalicular bile salt export pump (BSEP) of hepatocyte. Liver transplantation is usually required. 4-phenylbutyrate (4-PB) has been shown in vitro to retarget some selected mutated apical transporters. After an in vitro study in a hepatocellular polarized line, we tested 4-PB treatment in a child with a homozygous p.T1210P BSEP mutation.
  
  
  METHODS
  Can 10 cells were transfected with plasmids encoding wild type Bsep (Bsep(wt)) and mutated p.T1210P Bsep (Bsep(T1210P)), both tagged with GFP. Then, cells were treated with 4-PB at 37 or 27°C, immunostained and analyzed using confocal microscopy. The child received 4-PB orally in two divided doses and BSEP liver immunostaining was performed before and after 4-PB as well as bile analysis.
  
  
  RESULTS
  In Can 10 cells, in contrast to Bsep(wt)-GFP, Bsep(T1210P)-GFP was not detected at the canalicular membrane but in the endoplasmic reticulum. 4-PB as well as incubation at 27°C partially corrected Bsep(T1210P)-GFP targeting to the canalicular membrane, while combined treatments resulted in normal canalicular localization. In the child, we showed that 4-PB improved clinical and biological parameters of cholestasis and liver function. Also, canalicular expression of p.T1210P BSEP mutant was partially corrected as was biliary bile acid excretion.
  
  
  CONCLUSIONS
  The results illustrate for the first time the therapeutic potential of a clinically approved chaperone drug in a selected patient with PFIC2 and support that bile secretion improvement might be due to the ability of 4-PB to retarget mutated BSEP.
authors.affiliation: Pediatric Hepatology and National Reference Centre for Rare Pediatric Liver Diseases, Bicêtre Universitary Hospital, Faculty of Medicine Paris-Sud, University of Paris-Sud 11, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gonzales
authors.forename: Brigitte
authors.initials: B
authors.lastname: Grosse
authors.forename: Doris
authors.initials: D
authors.lastname: Cassio
authors.forename: Anne
authors.initials: A
authors.lastname: Davit-Spraul
authors.forename: Monique
authors.initials: M
authors.lastname: Fabre
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Jacquemin
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001647:Bile Acids and Salts / Q000097:blood; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D002780:Cholestasis, Intrahepatic / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D020125:Mutation, Missense; D010654:Phenylbutyrates / Q000494:pharmacology / Q000627:therapeutic use*; D011537:Pruritus / Q000209:etiology
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid