Reiss Ulrike M, Davidoff Andrew M, Tuddenham Edward G D, Chowdary Pratima, McIntosh Jenny, Muczynski Vincent, Journou Malo, Simini Giulia, Ireland Lydia, Mohamed Saira, Riddell Anne, Pie Arnulfo J, Hall Andrew, Quaglia Alberto, Mangles Sarah, Mahlangu Johnny, Haley Kristina, Recht Michael, Shen Yu-Min, Halka Kathleen G, Fortner Gail, Morton Christopher L, Gu Zhengming, Hayden Randall T, Neufeld Ellis J, Okhomina Victoria I, Kang Guolian, Nathwani Amit C
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN.
Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN.
N Engl J Med. 2025 Jun 12;392(22):2226-2234. doi: 10.1056/NEJMoa2414783.
Adeno-associated virus (AAV)-mediated gene therapy has emerged as a promising treatment for hemophilia B. Data on safety and durability from 13 years of follow-up in a cohort of patients who had been successfully treated with scAAV2/8-LP1-hFIXco gene therapy are now available.
Ten men with severe hemophilia B received a single intravenous infusion of the scAAV2/8-LP1-hFIXco vector in one of three dose groups (low-dose: 2×10 vector genomes [vg] per kilogram of body weight [in two participants]; intermediate-dose: 6×10 vg per kilogram [in two]; or high-dose: 2×10 vg per kilogram [in six]). Efficacy outcomes included factor IX activity, the annualized bleeding rate, and factor IX concentrate use. Safety assessments included clinical events, liver function, and imaging.
Participants were followed for a median of 13.0 years (range, 11.1 to 13.8). Factor IX activity remained stable across the dose cohorts, with mean factor IX levels of 1.7 IU per deciliter in the low-dose group, 2.3 IU per deciliter in the intermediate-dose group, and 4.8 IU per deciliter in the high-dose group. Seven of the 10 participants did not receive prophylaxis. The median annualized bleeding rate decreased from 14.0 episodes (interquartile range, 12.0 to 21.5) to 1.5 episodes (interquartile range, 0.7 to 2.2), which represented a reduction by a factor of 9.7. Use of factor IX concentrate decreased by a factor of 12.4 (interquartile range, 2.2 to 27.1). A total of 15 vector-related adverse events occurred, primarily transient elevations in aminotransferase levels. Factor IX inhibitor, thrombosis, or chronic liver injury did not develop in any participant. Two cancers were identified but were deemed by the investigators, together with an expert multidisciplinary team, as being unrelated to the vector. A liver biopsy that was conducted in 1 participant 10 years after the infusion revealed transcriptionally active transgene expression in hepatocytes without fibrosis or dysplasia. Levels of neutralizing antibodies to AAV8 remained high throughout follow-up, thus indicating potential barriers to readministration of the vector.
A single administration of scAAV2/8-LP1-hFIXco gene therapy resulted in durable factor IX expression, sustained clinical benefit, and no late-onset safety concerns over a period of 13 years. These data support the long-term efficacy and safety of AAV gene therapy for severe hemophilia B. (Funded by the U.K. Medical Research Council and others; ClinicalTrials.gov number, NCT00979238; EudraCT number, 2005-005711-17.).
腺相关病毒（AAV）介导的基因疗法已成为治疗B型血友病的一种有前景的方法。目前已有一组成功接受scAAV2/8-LP1-hFIXco基因疗法治疗的患者13年随访的安全性和持久性数据。
10名重度B型血友病男性患者接受了scAAV2/8-LP1-hFIXco载体的单次静脉输注，分为三个剂量组之一（低剂量组：每千克体重2×10载体基因组[vg] [2名参与者]；中剂量组：每千克6×10 vg [2名]；高剂量组：每千克2×10 vg [6名]）。疗效指标包括凝血因子IX活性、年化出血率和凝血因子IX浓缩剂使用情况。安全性评估包括临床事件、肝功能和影像学检查。
参与者的中位随访时间为13.0年（范围11.1至13.8年）。各剂量组的凝血因子IX活性保持稳定，低剂量组平均凝血因子IX水平为每分升1.7 IU，中剂量组为每分升2.3 IU，高剂量组为每分升4.8 IU。10名参与者中有7名未接受预防性治疗。年化出血率中位数从14.0次（四分位间距12.0至21.5）降至1.5次（四分位间距0.7至2.2），降幅达9.7倍。凝血因子IX浓缩剂的使用减少了12.4倍（四分位间距2.2至27.1）。共发生15起与载体相关的不良事件，主要是转氨酶水平短暂升高。所有参与者均未出现凝血因子IX抑制剂、血栓形成或慢性肝损伤。发现了2例癌症，但研究者与专家多学科团队认为这些癌症与载体无关。1名参与者在输注后10年进行的肝活检显示，肝细胞中转基因表达具有转录活性，无纤维化或发育异常。在整个随访期间，针对AAV8的中和抗体水平一直很高，这表明再次给药可能存在潜在障碍。
单次给予scAAV2/8-LP1-hFIXco基因疗法可使凝血因子IX表达持久，临床获益持续，且在13年期间无迟发性安全问题。这些数据支持了AAV基因疗法治疗重度B型血友病的长期疗效和安全性。（由英国医学研究理事会等资助；ClinicalTrials.gov编号，NCT00979238；欧盟临床试验注册号，2005-005711-17。）
