Mutation specific drug therapy for progressive familial or benign recurrent intrahepatic cholestasis: A new tool in a near future?

Mutation specific drug therapy in PFIC/BRIC. Identification of the mutation class (nonsense, missense), assessment of the canalicular membrane expression in vivo of the mutant protein (immunohistochemistry), in vitro study of the protein trafficking/proteasomal degradation, of residual function of the mutated protein as well as of the effect of various drugs, constitute the rational to guide a mutation specific drug therapy strategy. Read through premature stop codon (mainly UGA) by drugs (e.g. aminoglycosides, PTC124), endoplasmic reticulum associated degradation (ERAD) inhibition by ERAD inhibitors (e.g. MG132), correction of protein misfolding by chaperone drugs (e.g. 4-PBA, curcumin), and increased gene transcription by nuclear receptor agonists (e.g. 6-ECDCA, fibrates, statins), are different approaches that could be used to render possible, sufficient expression of a functional protein at the canalicular membrane.