Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy
Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy
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DOI：
10.1172/jci57291
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发表时间：
2011-08-01
影响因子：
15.9
通讯作者：
Monani, Umrao R.
中科院分区：
文献类型：
--
作者：
Lutz, Cathleen M.;Kariya, Shingo;Monani, Umrao R.
脊髓性肌萎缩症（SMA）是人类常见的神经肌肉疾病。事实上，它是婴儿死亡率最常见的遗传原因，是运动神经元1（SMN 1）基因突变的结果，降低了SMN蛋白的水平。在SMA患者中恢复SMN蛋白水平被认为是一种可行的治疗选择，但一旦症状明显，这种策略的疗效尚未确定。我们已经产生了小鼠携带诱导型Smn救援等位基因，并将其用于SMA模型中，以研究在疾病过程中的不同时间点开启SMN表达的影响。即使在疾病发作后恢复SMN蛋白也足以逆转神经肌肉病理学，并有效挽救SMA表型。重要的是，我们的研究结果还表明，从P4到P8有一个治疗的机会窗口，由神经肌肉突触病理学的程度和运动神经元对SMN诱导的反应能力定义，随后将蛋白质恢复到生物体未能产生治疗益处。然而，我们的研究结果表明，即使在严重的SMA中，及时恢复SMN蛋白可能会阻止疾病的进展，并作为一种有效的对症治疗。
Spinal muscular atrophy (SMA) is a common neuromuscular disorder in humans. In fact, it is the most frequently inherited cause of infant mortality, being the result of mutations in the survival of motor neuron 1 (SMN1) gene that reduce levels of SMN protein. Restoring levels of SMN protein in individuals with SMA is perceived to be a viable therapeutic option, but the efficacy of such a strategy once symptoms are apparent has not been determined. We have generated mice harboring an inducible Smn rescue allele and used them in a model of SMA to investigate the effects of turning on SMN expression at different time points during the course of the disease. Restoring SMN protein even after disease onset was sufficient to reverse neuromuscular pathology and effect robust rescue of the SMA phenotype. Importantly, our findings also indicated that there was a therapeutic window of opportunity from P4 through P8 defined by the extent of neuromuscular synapse pathology and the ability of motor neurons to respond to SMN induction, following which restoration of the protein to the organism failed to produce therapeutic benefit. Nevertheless, our results suggest that even in severe SMA, timely reinstatement of the SMN protein may halt the progression of the disease and serve as an effective postsymptomatic treatment.