Hsieh Pei-Feng, Lai Hsing-Jung, Kuo Yih-Chih, Yang Chih-Chao, Huang Po-Ya, Ting Chen-Hung, Tai Shao-Ting, Kao Chia-Hsin, Tsai Yi-Chieh, Huang Hsi-Wen, Shieh Jeng-Yi, Chiou Han, Cheng Lo-Fan, Weng Wen-Chin, Tsai Li-Kai
Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan; Department of Neurology, National Taiwan University Hospital, Hsinchu Branch, Hsinchu City 300, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan.
Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
Exp Neurol. 2025 Jul;389:115230. doi: 10.1016/j.expneurol.2025.115230. Epub 2025 Apr 1.
Nusinersen treatment not only prevents neurological deterioration in presymptomatic or early symptomatic children with spinal muscular atrophy (SMA) but promotes functional improvement in the later plateau phase in adults with SMA, though the mechanisms for such functional improvement are not fully understood. We evaluated the motor behaviors and electrophysiological performance of 10 consecutive adult patients with SMA before and 2, 6, 10 months after nusinersen treatment. Adult SMA mice (SmnSMN2) were treated with nusinersen intracerebroventricularly for 2 months with analysis of the SMN transcripts and proteins expression, motor function, electrophysiology, and pathology of spinal cord and muscles. SMA patients showed motor function improvement in 10 months after nusinersen treatment with an increase in compound muscle action potential (CMAP) amplitude and motor unit number estimation (MUNE). Nusinersen augmented the expression of full-length SMN transcripts and proteins in SMA mice. SMA mice receiving nusinersen treatment showed a motor behavioral improvement with an increase in MUNE. Although nusinersen treatment partially prevented spinal motor neuron death, there was no obvious elevation in motor neuron density despite an increase in MUNE, indicating the reactivation of quiescent motor neurons. Nusinersen treatment not only eliminated progressive denervation at the neuromuscular junction (NMJ), but also promoted NMJ innervation, implying the existence of reinnervation. The functional improvements observed with nusinersen treatment in adults with SMA during the later plateau phase primarily result from two mechanisms: the revival of live but functionless motor neurons and the reinnervation of NMJs through axonal sprouting and the formation of new motor units.
诺西那生治疗不仅可预防脊髓性肌萎缩症（SMA）症状前或症状早期儿童的神经功能恶化，还能促进SMA成年患者在疾病后期平台期的功能改善，尽管这种功能改善的机制尚未完全明确。我们评估了10例连续性成年SMA患者在接受诺西那生治疗前以及治疗后2个月、6个月和10个月时的运动行为和电生理表现。对成年SMA小鼠（SmnSMN2）进行脑室内注射诺西那生治疗2个月，并分析其SMN转录本和蛋白表达、运动功能、电生理以及脊髓和肌肉的病理学变化。SMA患者在接受诺西那生治疗10个月后运动功能得到改善，复合肌肉动作电位（CMAP）幅度和运动单位数量估计（MUNE）增加。诺西那生可增强SMA小鼠全长SMN转录本和蛋白的表达。接受诺西那生治疗的SMA小鼠运动行为得到改善，MUNE增加。尽管诺西那生治疗部分预防了脊髓运动神经元死亡，但尽管MUNE增加，运动神经元密度并未明显升高，这表明静止的运动神经元被重新激活。诺西那生治疗不仅消除了神经肌肉接头（NMJ）处进行性失神经支配，还促进了NMJ的神经支配，这意味着存在神经再支配现象。在SMA成年患者疾病后期平台期观察到的诺西那生治疗带来的功能改善主要源于两种机制：存活但无功能的运动神经元的复苏以及通过轴突发芽和新运动单位的形成实现NMJ的神经再支配。
