用努西森治疗婴儿发作的脊柱肌肉缩:第二阶段的开放性剂量升级研究

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Evaluation of Exon Inclusion Induced by Splice Switching Antisense Oligonucleotides in SMA Patient Fibroblasts

Published on: May 11, 2018

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Richard S Finkel¹, Claudia A Chiriboga², Jiri Vajsar³

¹Nemours Children's Hospital, Orlando, FL, USA.

Lancet (London, England)

|December 13, 2016

概括

在第二阶段的研究中,Nusinersen治疗脊柱肌肉缩 (SMA) 的安全性和有效性得到了证明. 该药物增加了生存运动神经元 (SMN) 蛋白质,改善了SMA婴儿的运动功能和生存率.

科学领域:

神经学
遗传学
药理学

背景情况:

脊髓肌肉缩 (SMA) 是一种遗传性疾病,其特征是功能生存运动神经元 (SMN) 蛋白质的缺乏.
努辛森是一种旨在通过改变SMN2前mRNA拼接来增加SMN蛋白水平的抗意义药物.

研究的目的:

评估Nusinersen在婴儿中多次注射的安全性,耐受性,药理动力学和临床疗效.
评估药物对运动功能,生存和SMN蛋白水平的影响.

主要方法:

这是一项开放式的第二阶段临床试验,涉及20名患有婴儿期SMA的婴儿.
纳西森的内注射 (6 mg 和 12 mg 的剂量等价物).
评估包括不良事件,神经检查,运动功能测试 (HINE-2,CHOP-INTEND),复合运动作用潜力,以及对目标接触的解剖分析.

主要成果:

所有参与者都出现了不良事件,但严重的不良事件被认为与nusinersen无关或不太可能相关.
在12毫克剂量组中,运动里程碑,CHOP- INTEND分数和复合肌肉作用潜力显著改善.
死亡时的中位数年龄或永久通风没有达到,与自然史数据不同,尸检证实药物吸收和SMN蛋白增加.

结论:

在患有SMA的婴儿中,多次注射努辛森的安全性和耐受性被证明是可以接受的.
药物表现出与其作用机制一致的药理学,并鼓励临床疗效,包括改善运动功能和生存.
结果支持了随后的婴儿发病的SMA第三阶段研究的设计.

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