Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs
Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs
复制标题
DOI：
10.1515/bc.2011.045
复制
发表时间：
2011-04-01
影响因子：
3.7
通讯作者：
Corey, David R.
中科院分区：
文献类型：
--
作者：
Hu, Jiaxin;Gagnon, Keith T.;Corey, David R.
脊髓小脑性共济失调-3（也称为Machado-Joseph病）是由共济失调蛋白-3（ATX 3）蛋白的突变变体的表达引起的不可治愈的神经退行性疾病。抑制ATX 3的表达将提供一种治疗策略，但不加区别地抑制野生型和突变型ATX 3可能导致不期望的副作用。理想的沉默剂将阻断突变体ATX 3的表达，同时保持野生型ATX 3的表达完整。我们先前已经观察到靶向ATX 3 mRNA内扩增的CAG重复序列的肽核酸（PNA）缀合物阻断两个等位基因的表达。我们现在已经鉴定了能够抑制ATX 3表达的另外的PNA，其长度和缀合阳离子链的性质不同。我们还可以使用含有相对于CAG重复的一个或多个错配的双链RNA来实现有效的和选择性的抑制。缺乏阳离子结构域的抗CAG反义桥接核酸寡核苷酸是有效的抑制剂，但不是等位基因选择性的。ATX 3表达的等位基因选择性抑制剂为进一步开发和体内研究提供了选择性机制和有前途的先导化合物。
Spinocerebellar ataxia-3 (also known as Machado-Joseph disease) is an incurable neurodegenerative disorder caused by expression of a mutant variant of ataxin-3 (ATX3) protein. Inhibiting expression of ATX3 would provide a therapeutic strategy, but indiscriminant inhibition of both wild-type and mutant ATX3 might lead to undesirable side effects. An ideal silencing agent would block expression of mutant ATX3 while leaving expression of wild-type ATX3 intact. We have previously observed that peptide nucleic acid (PNA) conjugates targeting the expanded CAG repeat within ATX3 mRNA block expression of both alleles. We have now identified additional PNAs capable of inhibiting ATX3 expression that vary in length and in the nature of the conjugated cation chain. We can also achieve potent and selective inhibition using duplex RNAs containing one or more mismatches relative to the CAG repeat. Anti-CAG antisense bridged nucleic acid oligonucleotides that lack a cationic domain are potent inhibitors but are not allele-selective. Allele-selective inhibitors of ATX3 expression provide insights into the mechanism of selectivity and promising lead compounds for further development and in vivo investigation.