Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Center for Motor Neuron Biology and Disease, Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
Sci Transl Med. 2021 Jan 27;13(578). doi: 10.1126/scitranslmed.abb6871.
Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.
基因替换和前体 mRNA 剪接修饰疗法代表了神经肌肉疾病脊髓性肌萎缩症（SMA）的突破性基因靶向治疗方法，但治疗效果的可变机制尚不完全清楚。我们对在快速尸检中获得的严重婴儿期起病的人类 SMA 组织进行了检查，发现发育不成熟的运动神经元轴突仍然存在，其中许多轴突正在积极退化。我们在严重 SMA 的小鼠模型中也发现了类似的特征，其中运动轴突的径向生长和施万细胞包绕受损始于胚胎发生，并导致获得的少突胶质细胞髓鞘化轴突减少，从而在新生儿期阻碍运动轴突功能。未能包绕的轴突在出生后迅速退化，特别是将神经丝轻链蛋白释放到血液中。在小鼠运动神经元中恢复存活运动神经元蛋白（SMN）的表达，而不是在 Schwann 细胞或肌肉中恢复，可改善 SMA 运动轴突的发育和维持。在小鼠中，从出生后立即开始使用小分子剪接修饰剂治疗可增加已髓鞘化轴突的径向生长，但需要在子宫内治疗才能恢复轴突生长和相关成熟，防止随后的新生儿轴突退化，并增强运动轴突功能。这些数据共同揭示了婴儿期起病的 SMA 患者新生儿期恶化的细胞基础，并确定了更有效治疗的时间窗口。这些发现表明，尽量减少治疗延迟对于实现最佳治疗效果至关重要。
