Meyer Kathrin, Marquis Julien, Trüb Judith, Nlend Nlend Rachel, Verp Sonia, Ruepp Marc-David, Imboden Hans, Barde Isabelle, Trono Didier, Schümperli Daniel
Institute of Cell Biology, University of Bern, Baltzerstrasse 4, CH-3012 Bern, Switzerland.
Hum Mol Genet. 2009 Feb 1;18(3):546-55. doi: 10.1093/hmg/ddn382. Epub 2008 Nov 13.
In spinal muscular atrophy (SMA), the leading genetic cause of early childhood death, the survival motor neuron 1 gene (SMN1) is deleted or inactivated. The nearly identical SMN2 gene has a silent mutation that impairs the utilization of exon 7 and the production of functional protein. It has been hypothesized that therapies boosting SMN2 exon 7 inclusion might prevent or cure SMA. Exon 7 inclusion can be stimulated in cell culture by oligonucleotides or intracellularly expressed RNAs, but evidence for an in vivo improvement of SMA symptoms is lacking. Here, we unambiguously confirm the above hypothesis by showing that a bifunctional U7 snRNA that stimulates exon 7 inclusion, when introduced by germline transgenesis, can efficiently complement the most severe mouse SMA model. These results are significant for the development of a somatic SMA therapy, but may also provide new means to study pathophysiological aspects of this devastating disease.
脊髓性肌萎缩症（SMA）是幼儿期死亡的主要遗传病因，其中生存运动神经元1基因（SMN1）发生缺失或失活。与SMN1几乎相同的SMN2基因存在一个沉默突变，该突变会损害外显子7的利用及功能性蛋白质的产生。据推测，促进SMN2外显子7包含的疗法可能预防或治愈SMA。在细胞培养中，寡核苷酸或细胞内表达的RNA可刺激外显子7的包含，但缺乏SMA症状在体内得到改善的证据。在此，我们通过表明一种刺激外显子7包含的双功能U7小核仁RNA经种系转基因导入后可有效补充最严重的小鼠SMA模型，明确证实了上述假设。这些结果对于开发SMA体细胞疗法具有重要意义，同时也可能为研究这种毁灭性疾病的病理生理学方面提供新手段。
