摘要
RNA干扰(RNAi)是一种转录后基因沉默的信使RNA(mRNA)降解介导的保守机制。RNAi通常是由识别靶mRNA的碱基配对合成siRNA或shRNA,导致靶mRNA的降解作用。RNAi可以区分相差只有一个核苷酸的两个序列,赋予其靶基因RNAi高特异性。此属性被用来开发成一种称为“等位基因特异性RNA干扰”的特殊治疗策略,该策略致力于沉默导致显性遗传性疾病突变等位基因,而不影响正常等位基因。治疗效果现在从患者和动物模型的细胞中表现出来,基于等位基因特异性siRNA Ib治疗先天性甲肥厚(一种由于Keratin 6基因显性突变引起的遗传性皮肤病)临床试验第一阶段的结果报道。我们的目的是总结治疗显性遗传性疾病治疗策略的成功案例,并避免困难。
关键词: 等位基因特异性沉默,显性遗传性疾病,缺陷,核糖核酸干扰,单碱基置换,基因治疗。
Current Gene Therapy
Title:Therapy for Dominant Inherited Diseases by Allele-Specific RNA Interference: Successes and Pitfalls
Volume: 15 Issue: 5
Author(s): Delphine Trochet, Bernard Prudhon, Stéphane Vassilopoulos and Marc Bitoun
Affiliation:
关键词: 等位基因特异性沉默,显性遗传性疾病,缺陷,核糖核酸干扰,单碱基置换,基因治疗。
摘要: RNA interference (RNAi) is a conserved mechanism for post-transcriptional gene silencing mediated by messenger RNA (mRNA) degradation. RNAi is commonly induced by synthetic siRNA or shRNA which recognizes the targeted mRNA by base pairing and leads to target-mRNA degradation. RNAi may discriminate between two sequences only differing by one nucleotide conferring a high specificity of RNAi for its target mRNA. This property was used to develop a particular therapeutic strategy called “allele-specific-RNA interference” devoted to silence the mutated allele of genes causing dominant inherited diseases without affecting the normal allele. Therapeutic benefit was now demonstrated in cells from patients and animal models, and promising results of the first phase Ib clinical trial using siRNA-based allele-specific therapy were reported in Pachyonychia Congenita, an inherited skin disorder due to dominant mutations in the Keratin 6 gene. Our purpose is to review the successes of this strategy aiming to treat dominant inherited diseases and to highlight the pitfalls to avoid.
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Trochet Delphine, Prudhon Bernard, Vassilopoulos Stéphane and Bitoun Marc, Therapy for Dominant Inherited Diseases by Allele-Specific RNA Interference: Successes and Pitfalls, Current Gene Therapy 2015; 15 (5) . https://dx.doi.org/10.2174/1566523215666150812115730
DOI https://dx.doi.org/10.2174/1566523215666150812115730 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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