Benemei Silvia, Gatto Francesca, Marcucci Rossella, Gresele Paolo
Medical Affairs, Pfizer Italia, Rome, Italy.
Department of Experimental and Clinical Medicine, University of Florence and Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy.
Thromb Haemost. 2025 Jun;125(6):513-522. doi: 10.1055/a-2413-4345. Epub 2024 Sep 11.
Gene therapy is a promising therapeutic approach for treating life-threatening disorders. Despite the clinical improvements observed with gene therapy, immune responses either innate or adaptive against the vector used for gene delivery, can affect treatment efficacy and lead to adverse reactions. Thrombotic microangiopathy (TMA) is a thrombosis with thrombocytopenia syndrome (TTS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and small vessel occlusion known to be elicited by several drugs, that has been recently reported as an adverse event of adeno-associated virus (AAV)-based gene therapy. TMA encompasses a heterogenous group of disorders, its classification and underlining mechanisms are still uncertain, and still lacks validated biomarkers. The identification of predictors of TMA, such as vector dose and patient characteristics, is a pressing need to recognize patients at risk before and after AAV-based gene therapy administration. This review aims to explore the literature on TMA associated with AAV-based gene therapy in the larger context of TMA (i.e., hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and other drug-related TMAs). Considering the wide attention recently gained by another TTS associated with a non-gene therapy viral platform (adenovirus, AV COVID-19 vaccine), namely vaccine-induced immune thrombocytopenia and thrombosis (VITT), AAV gene therapy-related TMA mechanisms will be discussed and differentiated from those of VITT to avoid recency bias and favor a correct positioning of these two recently emerged syndromes within the heterogenous group of drug-related TTS. Finally, the review will discuss strategies for enhancing the safety and optimize the management of AAV-based gene therapy that is emerging as an efficacious therapeutic option for disparate, severe, and often orphan conditions.
基因治疗是一种治疗危及生命疾病的有前景的治疗方法。尽管基因治疗取得了临床进展，但针对用于基因递送的载体的先天性或适应性免疫反应，可能会影响治疗效果并导致不良反应。血栓性微血管病（TMA）是一种伴有血小板减少症的血栓形成综合征（TTS），其特征为微血管病性溶血性贫血、血小板减少和小血管闭塞，已知由多种药物引发，最近被报道为基于腺相关病毒（AAV）的基因治疗的不良事件。TMA涵盖一组异质性疾病，其分类和潜在机制仍不确定，且仍缺乏经过验证的生物标志物。识别TMA的预测因素，如载体剂量和患者特征，是在基于AAV的基因治疗给药前后识别有风险患者的迫切需求。本综述旨在在TMA（即溶血尿毒综合征、血栓性血小板减少性紫癜和其他药物相关的TMA）的更大背景下，探讨与基于AAV的基因治疗相关的TMA的文献。考虑到另一种与非基因治疗病毒平台（腺病毒，AV COVID-19疫苗）相关的TTS，即疫苗诱导的免疫性血小板减少和血栓形成（VITT）最近受到广泛关注，将讨论AAV基因治疗相关的TMA机制，并与VITT的机制进行区分，以避免近期偏差，并有利于在异质性药物相关TTS组中正确定位这两种最近出现的综合征。最后，本综述将讨论提高基于AAV的基因治疗安全性和优化管理的策略，这种治疗正成为治疗各种严重且通常为罕见疾病的有效治疗选择。
