Precision Gene-Based Therapy for Progressive Familial Intrahepatic Cholestasis: Matching Platform to Disease Biology

Progressive familial intrahepatic cholestasis (PFIC) encompasses genetically heterogeneous disorders affecting bile transport, membrane organisation, epithelial polarity and bile-acid signalling. Current medical and surgical treatments can improve symptoms and disease course in selected patients, but substantial unmet need remains, particularly in severe early-onset disease and multisystem disorders. This review considers the thirteen numbered PFIC subtypes and selected related monogenic cholestatic conditions, relating their mechanisms to gene addition, genome editing, splice correction, messenger RNA replacement and cell-based strategies. Published PFIC intervention evidence is predominantly preclinical, with proof of concept in selected mouse models and in vitro systems. Clinical experience in other liver diseases provides relevant delivery and safety precedents but does not establish efficacy in PFIC. Platform selection will depend on molecular mechanism, target tissue, therapeutic threshold, disease stage and the durability required during liver growth. Severe disease identifies unmet need rather than a proven optimal platform. We propose a framework for research prioritisation and identify the studies needed to establish sustained benefit, genomic and immunological safety, and clinically meaningful outcomes.