Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy
Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy
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DOI：
10.1172/jci200422922
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发表时间：
2004-12-01
影响因子：
15.9
通讯作者：
Mazarakis, ND
中科院分区：
文献类型：
--
作者：
Azzouz, M;Le, T;Mazarakis, ND
脊髓性肌萎缩症（SMA）是一种常见的隐性常染色体疾病。它是由运动神经元存活（SMN）基因端粒拷贝突变或缺失引起的，导致SMN蛋白水平耗竭。SMA的治疗原理是停止或延迟运动神经元的变性，但迄今为止，尚无有效的药物治疗这种疾病。我们以前已经证明，假型的非灵长类马传染性贫血病毒（使用lentivector基因转移系统）与狂犬病病毒的伊夫林-Rokitnicki-Abelseth株的糖蛋白赋予这些载体上的逆行轴突运输。在这里，我们报告了表达人SMN的慢病毒载体成功地用于恢复SMA 1型成纤维细胞中的SMN蛋白水平。在SMA小鼠的各种肌肉中多次单次注射表达SMN的慢病毒载体使SMN恢复为运动神经元，减少运动神经元死亡，并且与LacZ和未治疗的动物相比，预期寿命分别平均增加3天和5天（20%和38%）。通过SMN表达构建体进一步延长存活可能需要了解何时和/或何处需要高水平的SMN。
Spinal muscular atrophy (SMA) is a frequent recessive autosomal disorder. It is caused by mutations or deletion of the telomeric copy of the survival motor neuron (SMN) gene, leading to depletion in SMN protein levels. The treatment rationale for SMA is to halt or delay the degeneration of motor neurons, but to date there are no effective drug treatments for this disease. We have previously demonstrated that pseudotyping of the nonprimate equine infectious anemia virus (using the lentivector gene transfer system) with the glycoprotein of the Evelyn-Rokitnicki-Abelseth strain of the rabies virus confers retrograde axonal transport on these vectors. Here, we report that lentivector expressing human SMN was successfully used to restore SMN protein levels in SMA type 1 fibroblasts. Multiple single injections of a lentiviral vector expressing SMN in various muscles of SMA mice restored SMN to motor neurons, reduced motor neuron death, and increased the life expectancy by an average of 3 and 5 days (20% and 38%) compared with LacZ and untreated animals, respectively. Further extension of survival by SMN expression constructs will likely require a knowledge of when and/or where high levels of SMN are needed.