Laforet Genevieve A
BridgeBio Gene Therapy, Palo Alto, California, USA.
Hum Gene Ther. 2025 Feb;36(3-4):64-76. doi: 10.1089/hum.2024.156. Epub 2025 Jan 16.
Complement-mediated thrombotic microangiopathy (TMA) in the form of atypical hemolytic uremic syndrome (aHUS) has emerged as an immune complication of systemic adeno-associated virus (AAV) gene transfer that was unforeseen based on nonclinical studies. Understanding this phenomenon in the clinical setting has been limited by incomplete data and a lack of uniform diagnostic and reporting criteria. While apparently rare based on available information, AAV-associated TMA/aHUS can pose a substantial risk to patients including one published fatality. Reported cases were originally limited to pediatric Duchenne muscular dystrophy patients receiving micro- or mini-dystrophin transgenes via AAV9 but have subsequently been reported in both pediatric and adult patients across a range of disorders, transgenes, promoters, and AAV capsid types. This article provides an introduction to the complement system, TMA and aHUS, and anticomplement therapies, then presents clinical reviews of AAV-associated TMA/aHUS cases that have been reported publicly. Finally, exploration of risk factors and current and future mitigation approaches are discussed.
以非典型溶血性尿毒症综合征（aHUS）形式出现的补体介导的血栓性微血管病（TMA）已成为系统性腺相关病毒（AAV）基因转移的一种免疫并发症，这是基于非临床研究未预见到的。临床环境中对这一现象的理解因数据不完整以及缺乏统一的诊断和报告标准而受到限制。根据现有信息，AAV相关的TMA/aHUS虽然明显罕见，但可能给患者带来重大风险，包括有一例已发表的死亡病例。报告的病例最初仅限于通过AAV9接受微型或小型抗肌萎缩蛋白转基因的儿童杜氏肌营养不良患者，但随后在患有一系列疾病、转基因、启动子和AAV衣壳类型的儿童和成人患者中均有报告。本文介绍了补体系统、TMA和aHUS以及抗补体疗法，然后对已公开报告的AAV相关TMA/aHUS病例进行了临床综述。最后，讨论了风险因素以及当前和未来的缓解方法。
