Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada, IDISNA, Universidad de Navarra, Pamplona, Spain.
Vivet Therapeutics, Pamplona, Spain.
Hum Gene Ther. 2019 Oct;30(10):1190-1203. doi: 10.1089/hum.2019.140.
In vertebrates, the liver is the central metabolic organ of the body, which carries out an estimated 500 functions that range from general detoxification to protein synthesis, bile production, metabolism of fats, carbohydrates, proteins, bilirubin, vitamin and mineral storage and it even has an immune function. Hepatocytes are considered the professional liver cells, which carry out all of these functions. With such a variety of tasks to perform, it is not surprising that more than 400 rare monogenic disorders of hepatic origin have been described. For many of these, liver transplantation remains the only curative strategy, however, this is limited by organ availability and requires lifelong immune suppression. The fact that liver transplantation is curative led to the assumption that the restoration of the expression of the defective gene would result in the resolution of the disease. Indeed, liver-directed gene therapy trials for hemophilia A and B have demonstrated the potential of gene therapy to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Thus, liver-directed gene therapy and gene editing strategies have emerged as promising alternatives to transplantation in inherited monogenic liver disorders. Herein, we review the advances and limitations of gene therapy for such disorders, covering therapeutic strategies based on gene addition and gene editing and the exciting clinical results obtained with the use of ribonucleic acid as therapeutic molecules.
在脊椎动物中，肝脏是身体的中央代谢器官，它执行着大约 500 种功能，从一般解毒到蛋白质合成、胆汁生成、脂肪、碳水化合物、蛋白质、胆红素、维生素和矿物质储存代谢，甚至具有免疫功能。肝细胞被认为是专业的肝脏细胞，执行所有这些功能。由于有如此多种类的任务要完成，毫不奇怪，已经描述了超过 400 种罕见的肝源性单基因疾病。对于其中许多疾病，肝移植仍然是唯一的治疗策略，然而，这受到器官可用性的限制，并且需要终身免疫抑制。肝移植是一种有效的治疗方法，这导致人们假设恢复缺陷基因的表达将导致疾病的缓解。事实上，针对血友病 A 和 B 的肝脏定向基因治疗试验已经证明了基因治疗在治疗单基因肝脏疾病方面具有提供长期临床益处的潜力。因此，肝脏定向基因治疗和基因编辑策略已成为遗传性单基因肝脏疾病的移植替代方法。本文综述了此类疾病的基因治疗的进展和局限性，涵盖了基于基因添加和基因编辑的治疗策略，以及使用 RNA 作为治疗分子获得的令人兴奋的临床结果。
