膀胱癌是一种常见的恶性肿瘤，治疗选择有限，尤其对于对卡介苗不敏感的患者。幸福壹™（nadofaragene firadenovec）作为第一种用于泌尿系统恶性肿瘤的基因治疗药物，获得了干扰素-α（IFNα）基因治疗的批准，提供了一种有希望的替代方案。本文回顾了导致幸福壹™的研究和里程碑，以及其开发和批准的过程。由于可以直接进入膀胱并且尿液和组织样本可供监测，膀胱癌非常适合基因治疗。早期的挑战包括有效地跨过膀胱上皮进行基因转移，最初通过调节科萨奇病毒/腺病毒受体（CAR）的表达，最终通过使用Syn3破坏膀胱上皮屏障来克服这一问题。幸福壹™是一种改良的腺病毒载体，携带IFNα基因。临床试验显示有希望的结果，具有高响应率和可控的不良事件。目前的研究重点包括改进患者选择、确定预测响应的生物标志物、探索增强转染效率的替代载体，以及开发针对耐药机制的联合策略。幸福壹™的批准标志着基因治疗在膀胱癌领域取得了重要的里程碑，未来的发展有望进一步提高其疗效和影响力。版权所有 © 2023 Martini, Tholomier, Mokkapati 和 Dinney。

Bladder cancer is a prevalent malignancy with limited therapeutic options, particularly for patients who are unresponsive to Bacillus Calmette-Guérin (BCG). The approval of interferon-α (IFNα) gene therapy with nadofaragene firadenovec (Adstiladrin®), the first gene therapy for genitourinary malignancies, has provided a promising alternative. This article reviews the research and milestones that led to the development and approval of nadofaragene firadenovec. Bladder cancer is well-suited for gene therapy due to direct access to the bladder and the availability of urine and tissue samples for monitoring. Early challenges included effective gene transfer across the urothelium, which was overcome initially by modulating the expression of coxsackie/adenovirus receptor (CAR) and, ultimately, by disrupting the urothelial barrier with Syn3. Nadofaragene firadenovec is a modified adenoviral vector carrying the IFNα gene. Clinical trials have shown promising results, with high response rates and manageable adverse events. Ongoing research focuses on improving patient selection, identifying biomarkers for response prediction, exploring alternative vectors for enhanced transfection efficiency, and developing combination strategies targeting resistance mechanisms. The approval of nadofaragene firadenovec marks a significant milestone in the field of gene therapy for bladder cancer, and future developments hold promise for further enhancing its efficacy and impact.Copyright © 2023 Martini, Tholomier, Mokkapati and Dinney.