Gene therapy for liver diseases: methods, challenges and opportunities.

Gene therapy has emerged as a promising and pivotal strategy for addressing numerous genetic disorders that currently lack effective therapeutic options. For many other presently incurable conditions, including the majority of inherited metabolic liver diseases, gene therapy offers a realistic and transformative treatment modality. This review highlights recent advancements in gene delivery vectors targeting the liver-specifically hepatocytes-with a focus on strategies involving gene supplementation and gene editing, as well as notable progress achieved through RNA-based therapeutic agents. Several early trials utilizing lipid nanoparticle (LNP)-based and recombinant adeno-associated virus (rAAV)-mediated approaches for gene supplementation and editing in liver diseases have yielded encouraging results. For example, rAAV-mediated FIX supplementation (2 × 1013 genome copies/kg) achieves sustained therapeutic activity in a subset of HOPE-B trial participants with hemophilia B, and LNP-CRISPR editing of ANGPTL3 (0.5 mg/kg mRNA) produces marked reductions in LDL-C and triglycerides. However, several translational challenges have been identified, including unintended activation of the innate immune system and severe hepatotoxicity following high-dose vector administration. These concerns necessitate rigorous and ongoing safety monitoring. In this review, we summarize major advancements, current challenges, and future perspectives in the field of liver-directed gene therapy. Additionally, we highlight key limitations inherent to existing approaches and discuss potential strategies to overcome these barriers and improve therapeutic outcomes.