Iascone Daniel M, Henderson Christopher E, Lee Justin C
Department of Rehabilitation and Regenerative Medicine, Center for Motor Neuron Biology and Disease, Columbia University Medical Center 630 West 168th Street, New York, NY 10032 USA ; Department of Neuroscience, Columbia Translational Neuroscience Initiative, Columbia University Medical Center 630 West 168th Street, New York, NY 10032 USA.
F1000Prime Rep. 2015 Jan 5;7:04. doi: 10.12703/P7-04. eCollection 2015.
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.
脊髓性肌萎缩症（SMA）是婴幼儿期最常见的遗传性死亡原因。所有脊髓性肌萎缩症病例均由存活运动神经元（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重点。我们探讨了在规划治疗成功时可能很重要的四个问题。第一，SMNΔ7小鼠模型中的神经肌肉表型与人类患者的表型密切匹配，但外周疾病表现有所不同，这表明除小鼠寿命外的其他终点可能在预测临床结果方面更有用。第二，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，目前尚不清楚这些细胞类型中哪些需要进行治疗靶向。第三，如果SMN恢复疗法并非对所有患者都有效，阻断SMN减少下游的分子变化可能会带来显著益处，因此评估除SMN之外的治疗靶点很重要。最后，对于疾病进展减缓但仍保留明显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有价值。
