近日，美国纽约大学Enrico Bertini团队研究了利司扑兰治疗症状前脊髓性肌萎缩症的疗效与安全性。2025年8月14日出版的《新英格兰医学杂志》发表这项最新成果。

利司扑兰是一种口服前信使RNA剪接修饰剂，是治疗症状性脊髓性肌萎缩症（SMA）的有效药物。利司扑兰治疗症状前疾病的安全性和有效性尚不清楚。

研究组进行了一项开放标签研究，对1天（出生）至42天的遗传诊断为SMA但没有强烈提示临床体征或症状的婴儿进行了每日口服利司扑兰（剂量调整为每公斤体重0.2 mg）的研究。在两个SMN2拷贝且基线尺复合肌动作电位（CMAP）振幅至少为1.5 mV的婴儿中，评估的主要结果是在12个月时无支撑坐的能力。自然史研究表明，大多数具有两个SMN2拷贝的婴儿如果未经治疗，将会有严重的SMA表型（1型），永远不能独坐，将接受永久性通气和喂养支持，或在13个月大时死亡。在24个月的时间里评估的次要结果包括生存、呼吸支持、运动里程碑、临床表现的SMA的发展、喂养和生长。

共有26名携带2个、3个或4个或更多SMN2拷贝的婴儿入组。经过12个月的治疗，21名婴儿（81%）可以在没有支撑的情况下坐30秒，14名（54%）可以独立站立，11名（42%）可以独立行走。5例婴儿中有4例(80%；95%置信区间为28 ~ 100)，两个SMN2拷贝，基线尺侧CMAP振幅至少为1.5 mV，可以在没有支持的情况下静坐至少5秒。在12个月的访问后，有三名婴儿被父母或照顾者从研究中撤出。在完成24个月治疗的23名婴儿中，没有使用永久性通气或喂养支持，所有婴儿都存活了下来。在24个月的时间里，7名婴儿报告了9起与治疗相关的不良事件；这些事件都不严重。

研究结果表明，在自然研究中，6周龄以下遗传诊断为SMA的婴儿在出现临床体征或症状之前接受利司扑兰治疗，在12个月和24个月时的功能和生存结果比未治疗的婴儿更好。需要更大规模、更长期随访的对照研究，以进一步了解利司扑兰在症状前治疗SMA的相对疗效和安全性。

附：英文原文

Title: Risdiplam in Presymptomatic Spinal Muscular Atrophy

Author: Richard S. Finkel, Laurent Servais, Dmitry Vlodavets, Edmar Zanoteli, Maria Mazurkiewicz-Bedzińska, Yuh-Jyh Jong, Aledie Navas-Nazario, Mohammad Al-Muhaizea, Alexandra P.Q.C. Araujo, Leslie Nelson, Yi Wang, Birgit Jaber, Ksenija Gorni, Heidemarie Kletzl, Laura Palfreeman, Michael Rabbia, Dave Summers, Eleni Gaki, Kathryn R. Wagner, Paulo Fontoura, Michelle A. Farrar, Enrico Bertini

Issue&Volume: 2025-08-14

Abstract:

Background

Risdiplam, an oral pre–messenger RNA splicing modifier, is an efficacious treatment for persons with symptomatic spinal muscular atrophy (SMA). The safety and efficacy of risdiplam in presymptomatic disease are unclear.

Methods

We conducted an open-label study of daily oral risdiplam (with the dose adjusted to 0.2 mg per kilogram of body weight) in infants 1 day (birth) to 42 days of age with genetically diagnosed SMA but without strongly suggestive clinical signs or symptoms. The primary outcome, assessed in infants with two SMN2 copies and a baseline ulnar compound muscle action potential (CMAP) amplitude of at least 1.5 mV, was the ability to sit without support at month 12. Natural history studies have shown that the majority of infants with two SMN2 copies who are untreated would have a severe SMA phenotype (type 1), would never sit independently, would receive permanent ventilation and feeding support, or would die by 13 months of age. Secondary outcomes that were assessed over a period of 24 months included survival, ventilatory support, motor milestones, the development of clinically manifested SMA, feeding, and growth.

Results

A total of 26 infants with two, three, or four or more copies of SMN2 were enrolled. After 12 months of treatment, 21 infants (81%) could sit unsupported for 30 seconds, 14 (54%) could stand alone, and 11 (42%) could walk alone. A total of 4 of 5 infants (80%; 95% confidence interval, 28 to 100) with two SMN2 copies and a baseline ulnar CMAP amplitude of at least 1.5 mV were able to sit without support for at least 5 seconds. Three infants were withdrawn from the study by a parent or caregiver after the month 12 visit. Of 23 infants who completed 24 months of treatment, all were alive without the use of permanent ventilation or feeding support. Over a period of 24 months, nine treatment-related adverse events were reported in 7 infants; none of these events were serious.

Conclusions

Infants up to 6 weeks of age with genetically diagnosed SMA who were treated with risdiplam before the development of clinical signs or symptoms appeared to have better functional and survival outcomes at 12 and 24 months than untreated infants in natural history studies. Larger, controlled studies with longer follow-up are needed to further understand the relative efficacy and safety of presymptomatic treatment of SMA with risdiplam.

DOI: NJ202508143930709

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2410120