Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
Neurobiol Dis. 2012 Jan;45(1):272-9. doi: 10.1016/j.nbd.2011.06.021. Epub 2011 Aug 18.
The efficacy of administering a recombinant adeno-associated virus (AAV) vector encoding human IGF-1 (AAV2/1-hIGF-1) into the deep cerebellar nucleus (DCN) of a type III SMA mouse model was evaluated. High levels of IGF-1 transcripts and protein were detected in the spinal cord at 2 months post-injection demonstrating that axonal connections between the cerebellum and spinal cord were able to act as conduits for the viral vector and protein to the spinal cord. Mice treated with AAV2/1-hIGF-1 and analyzed 8 months later showed changes in endogenous Bax and Bcl-xl levels in spinal cord motor neurons that were consistent with IGF-1-mediated anti-apoptotic effects on motor neurons. However, although AAV2/1-hIGF-1 treatment reduced the extent of motor neuron cell death, the majority of rescued motor neurons were non-functional, as they lacked axons that innervated the muscles. Furthermore, treated SMA mice exhibited abnormal muscle fibers, aberrant neuromuscular junction structure, and impaired performance on motor function tests. These data indicate that although CNS-directed expression of IGF-1 could reduce motor neuron cell death, this did not translate to improvements in motor function in an adult mouse model of type III SMA.
评估了向 III 型 SMA 小鼠模型的深部小脑核（DCN）中注射编码人 IGF-1 的重组腺相关病毒（AAV）载体（AAV2/1-hIGF-1）的疗效。在注射后 2 个月，脊髓中检测到高水平的 IGF-1 转录本和蛋白，表明小脑和脊髓之间的轴突连接能够作为病毒载体和蛋白向脊髓的传导途径。用 AAV2/1-hIGF-1 处理并在 8 个月后分析的小鼠显示，脊髓运动神经元中内源性 Bax 和 Bcl-xl 水平发生变化，这与 IGF-1 对运动神经元的抗凋亡作用一致。然而，尽管 AAV2/1-hIGF-1 治疗减少了运动神经元的死亡程度，但大多数被挽救的运动神经元没有功能，因为它们缺乏支配肌肉的轴突。此外，治疗后的 SMA 小鼠表现出异常的肌肉纤维、神经肌肉接头结构异常以及运动功能测试中的运动功能受损。这些数据表明，尽管中枢神经系统定向表达 IGF-1 可以减少运动神经元的死亡，但这并没有转化为 III 型 SMA 成年小鼠模型运动功能的改善。
