Azzouz Mimoun, Le Thanh, Ralph G Scott, Walmsley Lucy, Monani Umrao R, Lee Debbie C P, Wilkes Fraser, Mitrophanous Kyriacos A, Kingsman Susan M, Burghes Arthur H M, Mazarakis Nicholas D
Oxford BioMedicaLtd., Medwar Centre, Robert Robinson Avenue, The Oxford Science Park, Oxford OX4 4GA, UK.
J Clin Invest. 2004 Dec;114(12):1726-31. doi: 10.1172/JCI22922.
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.
脊髓性肌萎缩症（SMA）是一种常见的隐性常染色体疾病。它由生存运动神经元（SMN）基因的端粒拷贝发生突变或缺失引起，导致SMN蛋白水平降低。SMA的治疗原理是阻止或延缓运动神经元的退化，但迄今为止，针对这种疾病尚无有效的药物治疗方法。我们之前已经证明，用狂犬病病毒伊夫林-罗基特尼基-阿贝尔塞思毒株的糖蛋白对非灵长类马传染性贫血病毒进行假型化（使用慢病毒载体基因转移系统）可使这些载体具有逆行轴突运输能力。在此，我们报告，表达人SMN的慢病毒载体成功用于恢复1型SMA成纤维细胞中的SMN蛋白水平。在SMA小鼠的不同肌肉中多次单次注射表达SMN的慢病毒载体，可使运动神经元恢复SMN，减少运动神经元死亡，与注射LacZ和未治疗的动物相比，平均预期寿命分别延长3天和5天（分别延长20%和38%）。通过SMN表达构建体进一步延长生存期可能需要了解何时和/或何处需要高水平的SMN。
