Department of Veterinary Pathobiology, Bond Life Sciences Center, University of Missouri, Columbia MO, USA.
BMC Neurosci. 2009 Nov 30;10:142. doi: 10.1186/1471-2202-10-142.
Spinal Muscular Atrophy (SMA) is the leading genetic cause of infantile death. It is caused by the loss of functional Survival Motor Neuron 1 (SMN1). There is a nearly identical copy gene, SMN2, but it is unable to rescue from disease due to an alternative splicing event that excises a necessary exon (exon 7) from the majority of SMN2-derived transcripts. While SMNDelta7 protein has severely reduced functionality, the exon 7 sequences may not be specifically required for all activities. Therefore, aminoglycoside antibiotics previously shown to suppress stop codon recognition and promote translation read-through have been examined to increase the length of the SMNDelta7 C-terminus.
Here we demonstrate that subcutaneous-administration of a read-through inducing compound (TC007) to an intermediate SMA model (Smn-/-; SMN2+/+; SMNDelta7) had beneficial effects on muscle fiber size and gross motor function.
Delivery of the read-through inducing compound TC007 reduces the disease-associated phenotype in SMA mice, however, does not significantly extend survival.
脊髓性肌萎缩症（SMA）是婴儿死亡的主要遗传原因。它是由功能性运动神经元 1（SMN1）的丧失引起的。有一个几乎相同的基因拷贝 SMN2，但由于一个剪接事件从大多数 SMN2 衍生的转录本中切除了一个必需的外显子（外显子 7），它无法从疾病中恢复。虽然 SMNDelta7 蛋白的功能严重降低，但外显子 7 序列可能不是所有活性所必需的。因此，先前已显示抑制终止密码子识别并促进翻译通读的氨基糖苷类抗生素已被检查以增加 SMNDelta7 C 末端的长度。
在这里，我们证明了皮下给予通读诱导化合物（TC007）对中间 SMA 模型（Smn-/-; SMN2+/+; SMNDelta7）在肌肉纤维大小和总体运动功能方面具有有益的影响。
通读诱导化合物 TC007 的递送可降低 SMA 小鼠的疾病相关表型，但不能显著延长生存时间。
