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nusinersen或假对照治疗婴儿期发病的脊髓性肌萎缩
Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy


Richard S. Finkel ... 妇产科和儿科 • 2017.11.02
相关阅读
• nusinersen或假对照治疗婴儿期发病的脊髓性肌萎缩 • 脊髓性肌萎缩的单剂基因替代治疗

反义寡核苷酸药物治疗婴儿脊髓性肌萎缩

 

肖苒

中国医学科学院整形外科医院

 

进行性神经系统疾病使患者逐渐失去体能和生存希望,因此迫切需要治疗。但是对该类疾病有效的小分子药物研发困难,应用人工合成的反义寡核苷酸(antisense oligonucleotide,ASO)调节疾病相关基因的表达,成为一种治疗策略。

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摘要


背景

脊髓性肌萎缩是由运动神经元存活(survival motor neuron,SMN)蛋白水平不足引起的常染色体隐性神经肌肉疾病。nusinersen是一种反义寡核苷酸药物,它修饰SMN2基因的前信使RNA剪接,从而促进全长SMN蛋白的产生。

 

方法

为探讨nusinersen对于患脊髓性肌萎缩婴儿的疗效,我们进行了一项随机、双盲、设假对照的3期临床疗效和安全性试验。试验的主要终点是运动功能里程碑反应(根据哈默史密斯婴儿神经测试[Hammersmith Infant Neurological Examination]的结果判断)和无事件生存期(至死亡或需要长期辅助通气的时间);次要终点包括总生存期以及根据筛查时的病程对无事件生存期进行的亚组分析。只有试验主要终点的第一项在预设的中期分析中进行检验。为了将总体Ⅰ型错误率控制在0.05,主要终点的第二项和次要终点在最终分析时采用分级检验策略。

 

结果

在中期分析中,nusinersen组中达到运动功能里程碑反应的婴儿百分比显著高于对照组(21/51 [41%] vs. 0/27[0],P<0.001),这一结果使得本试验提前终止。在最终分析中,nusinersen组中达到运动功能里程碑反应的婴儿百分比显著高于对照组(37/73 [51%] vs. 0/37[0%]),无事件生存的可能性也高于对照组(死亡或长期辅助通气的风险比,0.53;P=0.005)。nusinersen组总的生存可能性高于对照组(死亡风险比,0.37;P=0.004),且与筛查时病程较长的婴儿相比,病程较短的婴儿更可能从nusinersen治疗中获益。两组中不良事件的发生率和严重程度相似。

 

结论

在患脊髓性肌萎缩的婴儿中,接受过nusinersen治疗的婴儿与对照组婴儿相比,运动功能有改善,且生存可能性较大。可能需要早期治疗以使药物效果最大化(由Biogen和Ionis Pharmaceuticals资助;ENDEAR在ClinicalTrials.gov注册号为NCT02193074)。





作者信息

Richard S. Finkel, M.D., Eugenio Mercuri, M.D., Ph.D., Basil T. Darras, M.D., Anne M. Connolly, M.D., Nancy L. Kuntz, M.D., Janbernd Kirschner, M.D., Claudia A. Chiriboga, M.D., M.P.H., Kayoko Saito, M.D., Ph.D., Laurent Servais, M.D., Ph.D., Eduardo Tizzano, M.D., Ph.D., Haluk Topaloglu, M.D., Már Tulinius, M.D., Ph.D., Jacqueline Montes, P.T., Ed.D., N.C.S., Allan M. Glanzman, P.T., D.P.T., P.C.S., Kathie Bishop, Ph.D., Z. John Zhong, Ph.D., Sarah Gheuens, M.D., Ph.D., C. Frank Bennett, Ph.D., Eugene Schneider, M.D., Wildon Farwell, M.D., M.P.H., and Darryl C. De Vivo, M.D., for the ENDEAR Study Group*
From the Division of Neurology, Department of Pediatrics, Nemours Children’s Hospital, Orlando, FL (R.S.F.); the Department of Pediatric Neurology, Catholic University, Rome (E.M.); the Department of Neurology, Boston Children’s Hospital, Boston (B.T.D.), and Biogen, Cambridge (Z.J.Z., S.G., W.F.) — both in Massachusetts; the Department of Neurology, St. Louis Children’s Hospital, St. Louis (A.M.C.); the Department of Pediatrics, Ann and Robert H. Lurie Children’s Hospital, Chicago (N.L.K.); the Department of Neuropediatrics and Muscle Disorders, Medical Center–University of Freiburg, Faculty of Medicine, Freiburg, Germany (J.K.); the Departments of Neurology (C.A.C., J.M.) and Rehabilitation and Regenerative Medicine (J.M.), Columbia University, and the Departments of Neurology and Pediatrics, Columbia University Medical Center (D.C.D.V.), New York; the Institute of Medical Genetics and Department of Pediatrics, Tokyo Women’s Medical University, Tokyo (K.S.); the Institute of Motion, Paris (L.S.); the Department of Clinical and Molecular Genetics and Rare Diseases Unit, Hospital Vall d’Hebron, and Centro de Investigacíon Biomédica en Red Enfermedades Raras (CIBERER), Barcelona (E.T.); the Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey (H.T.); the Department of Pediatrics, Gothenburg University, Queen Silvia Children’s Hospital, Gothenburg, Sweden (M.T.); the Department of Physical Therapy, Children’s Hospital of Philadelphia, Philadelphia (A.M.G.); and Ionis Pharmaceuticals, Carlsbad, CA (K.B., C.F.B., E.S.). Address reprint requests to Dr. Finkel at the Division of Neurology, Department of Pediatrics, Nemours Children’s Hospital, 13535 Nemours Pkwy., 5th Fl., Orlando, FL 32827, or at richard.finkel@nemours.org. *A complete list of the principal investigators in the ENDEAR trial is provided in the Supplementary Appendix, available at NEJM.org.

 

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