Spinal muscular atrophy: from tissue specificity to therapeutic strategies.
Spinal muscular atrophy: from tissue specificity to therapeutic strategies.
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脊柱肌肉萎缩：从组织特异性到治疗策略。
DOI：
10.12703/p7-04
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Lee JC
中科院分区：
文献类型：
--
作者：
Iascone DM;Henderson CE;Lee JC
脊髓性肌萎缩症（SMA）是婴儿和幼儿死亡的最常见遗传原因。脊髓性肌萎缩症的所有病例都是由于运动神经元存活（SMN）蛋白水平降低所致，因此SMN上调是许多临床前和临床研究的焦点。我们研究了四个问题，可能是重要的治疗成功的规划。首先，SMNΔ7小鼠模型中的神经肌肉表型与人类患者中的表型密切匹配，但外周疾病表现不同，这表明除小鼠寿命外的终点可能在预测临床结局方面更有用。其次，SMN在多种中枢和外周细胞类型中发挥重要作用，而不仅仅是运动神经元，目前还不清楚这些细胞类型中的哪一种需要治疗靶向。第三，如果SMN恢复治疗不是对所有患者都有效，那么阻断SMN减少下游的分子变化可能会带来显著的益处，因此评价SMN以外的治疗靶点非常重要。最后，对于疾病进展减缓但仍保留显著运动功能障碍的患者，用于增强神经肌肉系统再生的其他方法可能具有价值。
Spinal muscular atrophy (SMA) is the most frequent genetic cause of death in infants and toddlers. All cases of spinal muscular atrophy result from reductions in levels of the survival motor neuron (SMN) protein, and so SMN upregulation is a focus of many preclinical and clinical studies. We examine four issues that may be important in planning for therapeutic success. First, neuromuscular phenotypes in the SMNΔ7 mouse model closely match those in human patients but peripheral disease manifestations differ, suggesting that endpoints other than mouse lifespan may be more useful in predicting clinical outcome. Second, SMN plays important roles in multiple central and peripheral cell types, not just motor neurons, and it remains unclear which of these cell types need to be targeted therapeutically. Third, should SMN-restoration therapy not be effective in all patients, blocking molecular changes downstream of SMN reduction may confer significant benefit, making it important to evaluate therapeutic targets other than SMN. Lastly, for patients whose disease progression is slowed, but who retain significant motor dysfunction, additional approaches used to enhance regeneration of the neuromuscular system may be of value.