腺相关病毒载体表达 U7 snRNA 嵌合的反义 RNA 寡核苷酸促进全长 SMN 的恢复。
Restoration of full-length SMN promoted by adenoviral vectors expressing RNA antisense oligonucleotides embedded in U7 snRNAs.
机构信息
Department of Microbiology and Molecular Genetics, School of Medicine, University of California Irvine, Irvine, California, United States of America.
出版信息
PLoS One. 2009 Dec 8;4(12):e8204. doi: 10.1371/journal.pone.0008204.
BACKGROUND
Spinal Muscular Atrophy (SMA) is an autosomal recessive disease that leads to specific loss of motor neurons. It is caused by deletions or mutations of the survival of motor neuron 1 gene (SMN1). The remaining copy of the gene, SMN2, generates only low levels of the SMN protein due to a mutation in SMN2 exon 7 that leads to exon skipping.
METHODOLOGY/PRINCIPAL FINDINGS: To correct SMN2 splicing, we use Adenovirus type 5-derived vectors to express SMN2-antisense U7 snRNA oligonucleotides targeting the SMN intron 7/exon 8 junction. Infection of SMA type I-derived patient fibroblasts with these vectors resulted in increased levels of exon 7 inclusion, upregulating the expression of SMN to similar levels as in non-SMA control cells.
CONCLUSIONS/SIGNIFICANCE: These results show that Adenovirus type 5-derived vectors delivering U7 antisense oligonucleotides can efficiently restore full-length SMN protein and suggest that the viral vector-mediated oligonucleotide application may be a suitable therapeutic approach to counteract SMA.
背景
脊髓性肌萎缩症（SMA）是一种常染色体隐性疾病，导致运动神经元的特定丧失。它是由运动神经元生存 1 基因（SMN1）的缺失或突变引起的。由于 SMN2 外显子 7 中的突变导致外显子跳跃，基因的剩余拷贝 SMN2 仅产生低水平的 SMN 蛋白。
方法/主要发现：为了纠正 SMN2 剪接，我们使用腺病毒 5 型衍生载体表达针对 SMN 内含子 7/外显子 8 连接点的 SMN2-反义 U7 snRNA 寡核苷酸。用这些载体感染来自 SMA 型 I 的患者成纤维细胞，导致外显子 7 包含水平增加，上调 SMN 的表达，使其与非 SMA 对照细胞相似。
结论/意义：这些结果表明，携带 U7 反义寡核苷酸的腺病毒 5 型衍生载体可以有效地恢复全长 SMN 蛋白，并表明病毒载体介导的寡核苷酸应用可能是一种治疗 SMA 的合适方法。
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