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Liver\u2010directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver\u2010targeting, including gene editing. We highlight the current development of viral and nonviral gene therapy for a number of inherited metabolic liver diseases including urea cycle defects, organic acidaemias, Crigler\u2013Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria and maple syrup urine disease. We describe the main limitations and open questions for further gene therapy development: immunogenicity, inflammatory response, genotoxicity, gene therapy administration in a fibrotic liver. The follow\u2010up of a constantly growing number of gene therapy treated patients allows better understanding of its benefits and limitations and provides strategies to design safer and more efficacious treatments. Undoubtedly, liver\u2010targeting gene therapy offers a promising avenue for innovative therapies with an unprecedented potential to address the unmet needs of patients suffering from inherited metabolic diseases.<\/jats:p>","DOI":"10.1002\/jimd.12709","type":"journal-article","created":{"date-parts":[[2024,1,3]],"date-time":"2024-01-03T21:29:57Z","timestamp":1704317397000},"page":"9-21","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Liver\u2010directed gene therapy for inherited metabolic diseases"],"prefix":"10.1002","volume":"47","author":[{"given":"Julien","family":"Baruteau","sequence":"first","affiliation":[{"name":"Department of Paediatric Metabolic Medicine Great Ormond Street Hospital for Children NHS Trust  London UK"},{"name":"University College London Great Ormond Street Institute of Child Health  London UK"},{"name":"National Institute of Health Research Great Ormond Street Biomedical Research Centre 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