Successful mutation-specific chaperone therapy with 4-phenylbutyrate in a child with progressive familial intrahepatic cholestasis type 2

JOURNAL OF HEPATOLOGY

卷:57

Article

Gonzales, Emmanuel^1,2  Grosse, Brigitte²  Cassio, Doris²  Jacquemin, Emmanuel^1,2 

[1] Univ Paris 11, AP HP, Bicetre Univ Hosp,Fac Med Paris Sud, Pediat Hepatol & Natl Reference Ctr Rare Pediat L, Le Kremlin Bicetre, France

[2] Univ Paris 11, INSERM, UMR S757, Orsay, France

关键词: PFIC2;    ABCB11;    BSEP;    Can 10;   

DOI  :  10.1016/j.jhep.2012.04.017

来源: Elsevier

【 摘 要 】

Background & Aims: 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 degrees 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 degrees 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. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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