Urea cycle defects are severe inherited metabolic diseases with high unmet needs, which present a permanent risk of hyperammonaemic decompensation and subsequent acute death or neurological sequelae, when treated with conventional dietetic and medical therapies. Liver transplantation is currently the only curative option, but has the potential to be supplanted by highly effective gene therapy interventions without the attendant need for life-long immunosuppression or limitations imposed by donor liver supply. Over the last three decades, pioneering genetic technologies have been explored to circumvent the consequences of urea cycle defects, improve quality of life and long-term outcome: adenoviral vectors, adeno-associated viral (AAV) vectors, gene editing, genome integration and non-viral technology with messenger RNA (mRNA). In this review, we present a summarised view of this historical path, which include some seminal milestones of the gene therapy's epic. We provide an update about the state of the art of gene therapy technologies for urea cycle defects and the current advantages and pitfalls driving future directions for research and development. This article is protected by copyright. All rights reserved
