Moving towards treatments for spinal muscular atrophy: hopes and limits
Moving towards treatments for spinal muscular atrophy: hopes and limits
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DOI：
10.1517/14728214.2015.1041375
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发表时间：
2015-04
影响因子：
3.4
通讯作者：
B. Wirth;M. Barkats;C. Martinat;M. Sendtner;T. Gillingwater
中科院分区：
文献类型：
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作者：
B. Wirth;M. Barkats;C. Martinat;M. Sendtner;T. Gillingwater
脊髓性肌萎缩症（SMA）是引起神经肌肉变性的最常见和最具破坏性的遗传性疾病之一，已达到临床翻译的最前沿。SMA患者非常独特的遗传情况，缺乏功能性SMN 1，但携带错误剪接的SMN 2拷贝基因，创造了通过反义寡核苷酸或药物纠正SMN 2剪接的可能性。这两种策略在临床前试验中显示出令人印象深刻的结果，目前正在进行II-III期临床试验。使用AAV 9-SMN载体的SMN基因治疗方法也非常有前途，并已进入I期临床试验。然而，对SMA动物模型和患者的仔细分析揭示了一些需要非常认真对待的局限性，包括：i）成功治疗的时间窗有限，使得SMA的新生儿筛查成为强制性的; ii）多器官损害，需要全身性治疗;和iii）对联合疗法的潜在需求，这些疗法既可以提高SMN水平，又可以靶向在整个生命周期内保留/挽救运动神经元功能的途径。应对这些挑战对于治愈SMA可能至关重要，而不仅仅是改善症状，特别是在最严重的形式中。本文综述了目前在临床试验中的治疗方法，SMA治疗的希望，以及这些新方法的潜在局限性。
Spinal muscular atrophy (SMA), one of the most frequent and devastating genetic disorders causing neuromuscular degeneration, has reached the forefront of clinical translation. The quite unique genetic situation of SMA patients, who lack functional SMN1 but carry the misspliced SMN2 copy gene, creates the possibility of correcting SMN2 splicing by antisense oligonucleotides or drugs. Both strategies showed impressive results in pre-clinical trials and are now in Phase II-III clinical trials. SMN gene therapy approaches using AAV9-SMN vectors are also highly promising and have entered a Phase I clinical trial. However, careful analysis of SMA animal models and patients has revealed some limitations that need to be taken very seriously, including: i) a limited time-window for successful therapy delivery, making neonatal screening of SMA mandatory; ii) multi-organ impairment, requiring systemic delivery of therapies; and iii) a potential need for combined therapies that both increase SMN levels and target pathways that preserve/rescue motor neuron function over the lifespan. Meeting these challenges will likely be crucial to cure SMA, instead of only ameliorating symptoms, particularly in its most severe form. This review discusses therapies currently in clinical trials, the hopes for SMA therapy, and the potential limitations of these new approaches.