Department of Pediatrics, Ohio State University, Columbus, Ohio; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio.
Department of Pediatrics, Ohio State University, Columbus, Ohio; Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio; Department of Neurology, Ohio State University, Columbus, Ohio.
Pediatr Neurol. 2019 Nov;100:3-11. doi: 10.1016/j.pediatrneurol.2019.06.007. Epub 2019 Jun 13.
Spinal muscular atrophy is a devastating neurodegenerative autosomal recessive disease that results from survival of motor neuron 1 (SMN1) gene mutation or deletion. Patients with spinal muscular atrophy type 1 utilizing supportive care, which focuses on symptom management, never sit unassisted, and 75% die or require permanent ventilation by age 13.6 months. Onasemnogene abeparvovec (Zolgensma, formerly AVXS-101) is a gene replacement therapy comprising an adeno-associated viral vector containing the human SMN gene under control of the chicken beta-actin promoter. This therapy addresses the genetic root cause of the disease by increasing functional SMN protein in motor neurons and preventing neuronal cell death, resulting in improved neuronal and muscular function as previously demonstrated in transgenic animal models. In an open-label, one-arm, dose-escalation phase 1 trial, systemic administration of onasemnogene abeparvovec via a one-time infusion over one hour demonstrated improved motor function and survival in all infants symptomatic for spinal muscular atrophy type 1. Of the 12 patients who received the proposed therapeutic dose, 11 achieved independent sitting, two achieved independent standing, and two are able to walk. Most of these 12 patients remained free of respiratory supportive care. The only treatment-related adverse event observed was transient asymptomatic transaminasemia that resolved with a short course of prednisolone treatment. This review discusses the biological rationale underlying gene replacement therapy for spinal muscular atrophy, describes the onasemnogene abeparvovec clinical trial experience, and provides expert recommendations as a reference for the real-world use of onasemnogene abeparvovec in clinical practice. As of May 24, 2019, the Food and Drug Administration approved onasemnogene abeparvovec, the first gene therapy approved to treat children younger than two years with spinal muscular atrophy.
脊髓性肌萎缩症是一种毁灭性的神经退行性常染色体隐性疾病，由运动神经元 1（SMN1）基因突变或缺失引起。1 型脊髓性肌萎缩症患者采用支持性护理，重点是症状管理，从不独立坐立，75%的患者在 13.6 个月前死亡或需要永久性通气。onasemnogene abeparvovec（曾用名 AVXS-101）是一种基因替代疗法，由含有人类 SMN 基因的腺相关病毒载体组成，受鸡β-肌动蛋白启动子控制。这种疗法通过增加运动神经元中的功能性 SMN 蛋白并防止神经元细胞死亡，从而解决疾病的遗传根本原因，如以前在转基因动物模型中所证明的那样，改善神经元和肌肉功能。在一项开放标签、单臂、剂量递增的 1 期临床试验中，onasemnogene abeparvovec 通过一次性输注 1 小时进行全身给药，在所有 1 型脊髓性肌萎缩症有症状的婴儿中均显示出运动功能改善和生存延长。在接受建议治疗剂量的 12 名患者中，11 名实现了独立坐立，2 名实现了独立站立，2 名能够行走。这些患者中大多数无需呼吸支持治疗。唯一观察到的与治疗相关的不良事件是短暂的无症状氨基转移酶升高，短期泼尼松龙治疗即可缓解。本文讨论了脊髓性肌萎缩症基因替代疗法的生物学原理，描述了 onasemnogene abeparvovec 临床试验经验，并提供了专家建议，为 onasemnogene abeparvovec 在临床实践中的实际应用提供参考。截至 2019 年 5 月 24 日，美国食品和药物管理局批准了 onasemnogene abeparvovec，这是第一种批准用于治疗 2 岁以下脊髓性肌萎缩症儿童的基因疗法。
