Tailor-made RNAi knockdown against triplet repeat disease-causing alleles
Tailor-made RNAi knockdown against triplet repeat disease-causing alleles
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DOI：
10.1073/pnas.1012153107
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发表时间：
2010-12-14
影响因子：
11.1
通讯作者：
Hohjoh, Hirohiko
中科院分区：
文献类型：
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作者：
Takahashi, Masaki;Watanabe, Shoko;Hohjoh, Hirohiko
疾病基因编码区的核苷酸变异（包括SNP）是RNAi治疗的重要靶点，RNAi是治疗三联体重复疾病等疑难杂症的一种有前途的医学方法。然而，鉴定此类核苷酸变异以及设计赋予疾病等位基因特异性 RNAi 的 siRNA 是相当困难的。在这项研究中，我们开发了一种下拉方法来快速识别三重重复、致病等位基因的编码SNP (cSNP)单倍型，并且我们证明了针对突变亨廷顿等位基因中的cSNP位点的疾病等位基因特异性RNAi，每个突变等位基因都具有不同的cSNP单倍型。因此，本文提出的方法允许使用特定于疾病相关 cSNP 单倍型的 siRNA 来对致病等位基因进行等位基因特异性 RNAi 敲除，并在三联体重复疾病的定制 RNAi 治疗方面取得进展。
Nucleotide variations, including SNPs, in the coding regions of disease genes are important targets for RNAi treatment, which is a promising medical treatment for intractable diseases such as triplet repeat diseases. However, the identification of such nucleotide variations and the design of siRNAs conferring disease allele-specific RNAi are quite difficult. In this study we developed a pull-down method to rapidly identify coding SNP (cSNP) haplotypes of triple repeat, disease-causing alleles, and we demonstrated disease allele-specific RNAi that targeted cSNP sites in mutant Huntingtin alleles, each of which possessed a different cSNP haplotype. Therefore, the methods presented here allow for allele-specific RNAi knockdown against disease-causing alleles by using siRNAs specific to disease-linked cSNP haplotypes, and advanced progress toward tailor-made RNAi treatments for triplet repeat diseases.