Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London, UK.
Gene Therapy Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney and Sydney Children's Hospitals Network, Westmead, New South Wales, Australia.
J Inherit Metab Dis. 2024 Jan;47(1):50-62. doi: 10.1002/jimd.12609. Epub 2023 Apr 18.
Urea cycle defects (UCDs) 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 UCDs, improve quality of life and long-term outcomes: adenoviral vectors, adeno-associated viral vectors, gene editing, genome integration and non-viral technology with messenger RNA. In this review, we present a summarised view of this historical path, which includes some seminal milestones of the gene therapy's epic. We provide an update about the state of the art of gene therapy technologies for UCDs and the current advantages and pitfalls driving future directions for research and development.
尿素循环缺陷（UCD）是一种严重的遗传性代谢疾病，存在未满足的巨大医疗需求，患者在接受常规饮食和药物治疗时，存在持续性的高氨血症危象风险，进而导致急性死亡或神经系统后遗症。目前，肝移植是唯一的根治方法，但随着高效基因治疗干预措施的出现，这种方法可能会被取代，而无需终身免疫抑制或受供体肝脏供应的限制。在过去的三十年中，人们探索了开创性的基因技术来规避 UCD 的后果，提高生活质量和长期预后：腺病毒载体、腺相关病毒载体、基因编辑、基因组整合和非病毒技术与信使 RNA。在这篇综述中，我们总结了这一历史进程，包括基因治疗史诗中的一些重要里程碑。我们介绍了 UCD 基因治疗技术的最新进展，以及推动未来研究和发展方向的当前优势和挑战。
