Spinal muscular atrophy (SMA) is a devastating motor neuron disease that predominantly affects children and represents the most common cause of hereditary infant mortality. The condition results from deleterious variants in SMN1, which lead to depletion of the survival motor neuron protein (SMN). Now, 20 years after the discovery of this genetic defect, a major milestone in SMA and motor neuron disease research has been reached with the approval of the first disease-modifying therapy for SMA by US and European authorities — the antisense oligonucleotide nusinersen. At the same time, promising data from early-stage clinical trials of SMN1 gene therapy have indicated that additional therapeutic options are likely to emerge for patients with SMA in the near future. However, the approval of nusinersen has generated a number of immediate and substantial medical, ethical and financial implications that have the potential to resonate beyond the specific treatment of SMA. Here, we provide an overview of the rapidly evolving therapeutic landscape for SMA, highlighting current achievements and future opportunities. We also discuss how these developments are providing important lessons for the emerging second generation of combinatorial ('SMN-plus') therapies that are likely to be required to generate robust treatments that are effective across a patient's lifespan.

脊髓性肌萎缩症（SMA）是一种毁灭性的运动神经元疾病，主要影响儿童，是遗传性婴儿死亡的最常见原因。该疾病是由SMN1中的有害变异导致的，该变异导致生存运动神经元蛋白（SMN）耗竭。现在，在发现这种遗传缺陷后20年，随着美国和欧洲当局批准了针对SMA的首个疾病缓解疗法-反义寡核苷酸nusinersen，SMA和运动神经元疾病研究已达到了一个重要的里程碑。同时，来自SMN1早期临床试验的有希望的数据基因治疗已经表明，在不久的将来，SMA患者可能会出现更多的治疗选择。但是，nusinersen的批准已经产生了许多直接的，实质性的医学，伦理和财务影响，可能会在SMA的特殊治疗方法之外引起共鸣。在此，我们概述了SMA迅速发展的治疗前景，重点介绍了当前的成就和未来的机会。我们还将讨论这些进展如何为新兴的第二代组合（'SMN-plus'）治疗提供重要的经验教训，而第二代组合治疗可能会产生在患者生命周期内有效的有效治疗。