Spellman Rebecca G, Ha Leillani L, Da Silva Duarte Lepez Salomé, Arruda Elizabeth A, Rodrigues Emma, Swoboda Kathryn J, Alves Christiano R R
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Gene Ther. 2025 Apr 1. doi: 10.1038/s41434-025-00529-6.
The present study examines the safety profile of intravenous onasemnogene abeparvovec gene therapy in a real-world setting, both alone or in combination with intrathecal antisense oligonucleotide nusinersen therapy in two cohorts of patients with spinal muscular atrophy (SMA). The first cohort included eight presymptomatic infants treated solely with onasemnogene abeparvovec, while the second cohort comprised six symptomatic infants receiving onasemnogene abeparvovec and nusinersen co-therapy. All patients received the corticosteroid prednisolone coincident with gene therapy. Circulating alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were measured to determine potential hepatoxicity, the primary focus of this study. Elevated ALT and AST levels were observed in one pre-symptomatic and three symptomatic patients post-treatment. However, all values returned to normal levels within 3 months of onasemnogene abeparvovec injection. Nusinersen treatment received previously or coincident with gene therapy did not impact the transient elevation of liver transaminases. This study highlights the importance of early intervention with molecular treatments for SMA and indicates that prior or coincident treatment with nusinersen is unlikely to impact safety of onasemnogene apoparvovec and could theoretically improve clinical outcomes in symptomatic infants or in those with gene therapy delayed beyond the immediate neonatal period.
本研究在真实世界环境中考察了静脉注射onasemnogene abeparvovec基因疗法的安全性，该疗法单独使用，或与鞘内注射反义寡核苷酸nusinersen疗法联合，用于两个脊髓性肌萎缩症（SMA）患者队列。第一组包括仅接受onasemnogene abeparvovec治疗的8名无症状婴儿，而第二组包括6名接受onasemnogene abeparvovec和nusinersen联合治疗的有症状婴儿。所有患者在接受基因治疗的同时接受了皮质类固醇泼尼松龙治疗。测量循环中的丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平以确定潜在的肝毒性，这是本研究的主要关注点。在1名无症状患者和3名有症状患者治疗后观察到ALT和AST水平升高。然而，在注射onasemnogene abeparvovec后的3个月内，所有值均恢复到正常水平。先前接受或与基因治疗同时接受的nusinersen治疗并未影响肝转氨酶的短暂升高。本研究强调了对SMA进行分子治疗早期干预的重要性，并表明先前或同时使用nusinersen治疗不太可能影响onasemnogene apoparvovec的安全性，并且理论上可以改善有症状婴儿或基因治疗延迟至新生儿期之后的婴儿的临床结局。
