oxadiazoles and Cholestasis--Intrahepatic

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic mutations in ABCB11 encoding the canalicular bile salt export pump (BSEP). Nonsense mutations are responsible for the most severe phenotypes. The aim was to assess the ability of drugs to induce readthrough of six nonsense mutations (p.Y354X, p.R415X, p.R470X, p.R1057X, p.R1090X, and p.E1302X) identified in patients with PFIC2.. The ability of G418, gentamicin, and PTC124 to induce readthrough was studied using a dual gene reporter system in NIH3T3 cells. The ability of gentamicin to induce readthrough and to lead to the expression of a full-length protein was studied in human embryonic kidney 293 (HEK293), HepG2, and Can 10 cells using immunodetection assays. The function of the gentamicin-induced full-length protein was studied by measuring the [. This study constitutes a proof of concept for readthrough therapy in selected patients with PFIC2 with nonsense mutations.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; Cholestasis, Intrahepatic; Codon, Nonsense; Cohort Studies; Dogs; Gentamicins; HEK293 Cells; Hep G2 Cells; Humans; Madin Darby Canine Kidney Cells; Mice; NIH 3T3 Cells; Oxadiazoles; Phenylbutyrates; Signal Transduction; Transfection; Ursodeoxycholic Acid