Bile salt export pump (BSEP, encoded by ABCB11), an ABC transporter localized on the canalicular membrane (CM) of hepatocytes, mediates biliary excretion of bile acids (BA). Its dysfunction impairs bile formation, a liver condition called intrahepatic cholestasis (IC). PFIC2, the most severe form of IC caused by mutation in ABCB11, progresses to liver failure and death before adulthood. Currently, the only therapeutic approach is liver transplantation.
We have shown that PFIC2-causing mutations predominantly affect expression of BSEP on the CM but not its transport activity and then searched potential compounds to restore BSEP expression. Sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorder (UCD), was found as the candidate. Animal experiments and retrospective study in UCD patients indicated that treatment with NaPB increases BSEP expression on the CM and thereby its function. Clinical study in three PFIC2 patients showed that NaPB therapy markedly improved biochemical tests, clinical symptoms, and liver histology.
Based on these facts, we have started clinical trial to obtain approval for new indications of NaPB for PFIC2 (UMIN000024753) and clinical study to investigate therapeutic potency of NaPB in patients with IC other than PFIC2 (UMIN000027666).

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