Antisense-Mediated Exon Inclusion
Antisense-Mediated Exon Inclusion
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DOI：
10.1007/978-1-61779-767-5_20
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发表时间：
2012-01-01
期刊：
影响因子：
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通讯作者：
Krainer, Adrian R.
中科院分区：
文献类型：
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作者：
Hua, Yimin;Krainer, Adrian R.
基因突变引起的外显子跳跃是许多遗传性疾病的常见机制。纠正缺陷基因的异常剪接的实用方法是使用反义寡核苷酸（ASO）。剪接位点的识别和剪接的调控涉及多个正或负顺式作用元件和反式作用因子。AS 0与靶向前mRNA中的负性外显子的碱基配对阻断剪接阻遏物与该顺式元件的结合和/或破坏不利的二级结构;因此，阿索恢复外显子包含。例如，我们最近在培养的人细胞（包括患者成纤维细胞）以及SMA小鼠模型的外周组织和CNS中，在无细胞剪接试验中证明了适当的2 '-O-（2-甲氧基乙基）（莫伊）硫代磷酸酯修饰的ASO可以有效纠正运动神经元2（SMN 2）外显子7的剪接。这些ASO是SMA治疗的有前景的药物先导。
Exon skipping induced by gene mutations is a common mechanism responsible for many genetic diseases. A practical approach to correct the aberrant splicing of defective genes is to use antisense oligonucleotides (ASOs). The recognition of splice sites and the regulation of splicing involve multiple positive or negative cis-acting elements and trans-acting factors. Base-pairing of ASOs to a negative clement in a targeted pre-mRNA blocks the binding of splicing repressors to this cis-element and/or disrupts an unfavorable secondary structure; as a result, the ASO restores exon inclusion. For example, we have recently shown that appropriate 2'-O-(2-methoxyethyl) (MOE) phosphorothioate-modified ASOs can efficiently correct survival motor neuron 2 (SMN2) exon 7 splicing in a cell-free splicing assay, in cultured human cells-including patient fibroblasts-and in both peripheral tissues and the CNS of SMA mouse models. These ASOs are promising drug leads for SMA therapy.