FDA调查Zolgensma基因疗法的恶性肿瘤风险：3例肿瘤涉GLI1致癌基因
美国食品药品监管局（FDA）11月6日发布安全通报称，该局已收到多起上市后不良事件报告：接受基因疗法 Zolgensma 治疗脊髓性肌萎缩症（SMA）的患者出现恶性肿瘤，其中包括经确认与产品相关的插入性致癌病例，涉及 GLI1 基因。GLI1 是一种致癌基因，在过度表达或异常激活时可能引发癌症。
据 FDA 通报，上市后报告的肿瘤形成病例涉及中枢与外周神经系统、脊柱与脊柱旁区域以及肾脏。其中3例肿瘤与 GLI1 致癌基因相关：2例的肿瘤组织分子分析显示，Zolgensma 所用的腺相关病毒（AAV）载体 DNA 已整合进宿主基因组，构建体的启动子区域插入到了 GLI1 致癌基因的上游或内部；第3例中 GLI1 过度表达的机制仍在调查中。FDA 还提到，其他 AAV 载体项目也曾有两篇关于载体整合导致致癌的公开报告。
FDA 认定，肿瘤形成（包括恶性肿瘤）的风险同样适用于另一款同成分产品 Itvisma，因为两款产品使用相同的载体与构建体。Zolgensma 经静脉输注，用于治疗2岁以下 SMA 患儿，最初于2019年5月24日获批；Itvisma 经鞘内注射，用于治疗2岁及以上 SMA 患者，最初于2025年11月24日获批。截至通报时，Itvisma 尚无肿瘤形成病例报告。FDA 同时表示，正密切监测其他类似 AAV 载体基因疗法项目的同类风险。
FDA 表示，就已批准的用途而言，Zolgensma 与 Itvisma 的总体获益仍然大于其潜在风险；但该局正在调查这一已确认的、后果严重的肿瘤风险，并评估是否需要采取监管行动。两款产品现行美国说明书在「警告与注意事项」中写有「AAV 载体 DNA 整合进基因组存在理论上的致癌风险」。生产企业 Novartis 正在开展长期随访安全性研究，FDA 正在加快评估现行说明书与长期随访研究是否足以调查并降低这一风险。
FDA 提醒，接受这两款产品治疗的患者与临床试验参与者应接受肿瘤形成监测。若接受 Zolgensma 治疗的患者出现肿瘤，或需要报告其他疑似不良反应，医疗服务提供者可联系 Novartis 基因疗法公司（电话 1-833-828-3947），也可联系 FDA（电话 1-800-FDA-1088，或通过 FDA 的 MedWatch 不良事件报告系统报告）。
（来源：美国食品药品监管局）
FDA Investigating Serious Risk of Malignancy Linked to Zolgensma Gene Therapy
The U.S. Food and Drug Administration (FDA) said in a safety communication on November 6 that it has received postmarketing adverse event reports of malignancies in patients treated with Zolgensma, an adeno-associated virus (AAV) vector-based gene therapy for spinal muscular atrophy (SMA), including confirmed reports of product-related insertional oncogenesis involving the GLI1 gene. GLI1 is an oncogene that has the potential to cause cancer when overexpressed or abnormally activated.
According to the FDA, postmarketing reports of tumor formation include tumors of the central and peripheral nervous systems, spinal and paraspinal regions, and the kidney. Three cases involved tumors associated with the GLI1 oncogene. In two of those cases, molecular analysis of tumor tissue demonstrated Zolgensma AAV vector DNA integration into the host genome, with the promoter region of the construct inserted upstream of or within the GLI1 oncogene. The mechanism of GLI1 overexpression in the third case remains under investigation. The FDA also noted two published reports of AAV vector integration-driven oncogenesis in other programs.
The FDA has determined that the risk of neoplasia, including malignancy, applies to both onasemnogene abeparvovec products, because they contain the same vector and construct. Zolgensma, given by intravenous infusion, is indicated for pediatric patients less than 2 years of age with SMA and was first approved on May 24, 2019. Itvisma, given by intrathecal injection, is indicated for patients 2 years of age and older and was first approved on November 24, 2025. No cases of neoplasia following Itvisma administration have been reported to date, and the FDA said it is closely monitoring the same risk in other similar AAV vector-based gene therapy programs.
The agency said the overall benefits of Zolgensma and Itvisma continue to outweigh their potential risks for their approved uses, while it investigates the identified risk of neoplasia, including malignancy with serious outcomes, and evaluates whether regulatory action is appropriate. The current U.S. prescribing information for both products notes a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome under Warnings and Precautions. Novartis, the sponsor, is conducting long-term follow-up safety studies, and the FDA is expeditiously evaluating whether the current labeling and follow-up studies are adequate to investigate and mitigate the risk.
The FDA said patients and clinical trial participants receiving these products should be monitored for tumor formation. Healthcare providers can report a tumor in a patient receiving Zolgensma, or other suspected adverse reactions, to Novartis Gene Therapies at 1-833-828-3947, or to the FDA at 1-800-FDA-1088 or through the FDA MedWatch reporting system.
(Source: U.S. Food and Drug Administration)
来源：美国食品药品监管局
发布：GSM·美国（发布链接）
图片来源：图：美国食品药品监管局（FDA）总部大楼（美国政府官方图）。 / Photo: FDA headquarters building (U.S. government photo).
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