Gene therapy is poised to revolutionize modern medicine, with seemingly unlimited potential for treating and curing genetic disorders. For otherwise incurable indications, including most inherited metabolic liver disorders, gene therapy provides a realistic therapeutic option. In this Review, we discuss gene supplementation and gene editing involving the use of recombinant adeno-associated virus (rAAV) vectors for the treatment of inherited liver diseases, including updates on several ongoing clinical trials that are producing promising results. Clinical testing has been essential in highlighting many key translational challenges associated with this transformative therapy. In particular, the interaction of a patient’s immune system with the vector raises issues of safety and the duration of treatment efficacy. Furthermore, several serious adverse events after the administration of high doses of rAAVs suggest greater involvement of innate immune responses and pre-existing hepatic conditions than initially anticipated. Finally, permanent modification of the host genome associated with rAAV genome integration and gene editing raises concerns about the risk of oncogenicity that require careful evaluation. We summarize the main progress, challenges and pathways forward for gene therapy for liver diseases.
Gene therapy mediated by recombinant adeno-associated virus (rAAV) vectors has emerged as a therapeutic option, with inherited liver disorders being prime targets for this strategy.
The first gene therapy for haemophilia B has been approved by the FDA, another for haemophilia A is nearing approval, and trials of several other rAAV-based liver-targeted gene therapies have produced promising results.
High rAAV doses (>1 × 1014 vg/kg) seem to be associated with severe adverse effects, including hepatotoxicity and immune response-associated sequelae.
Due to the primarily non-integrative nature of rAAV genomes, loss of vector genomes during cell turnover is of essential concern for the durability of therapeutic effect, particularly in paediatric patients.
Gene-editing strategies offer the most powerful tools for permanently correcting genetic disorders via direct modification of the genome but pose additional safety risks, such as oncogenicity, owing to insertional mutagenesis.
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N.D.W. and G.G-A. are employees and shareholders of Vivet Therapeutics. The views expressed in this Review belong to the authors alone and do not reflect the opinions of Vivet Therapeutics. The other authors declare no competing interests.
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Zabaleta, N., Unzu, C., Weber, N.D. et al. Gene therapy for liver diseases — progress and challenges. Nat Rev Gastroenterol Hepatol 20, 288–305 (2023). https://doi.org/10.1038/s41575-022-00729-0