A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interference
A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interference
复制标题
DOI：
10.1016/j.expneurol.2009.03.004
复制
发表时间：
2009-06-01
影响因子：
5.3
通讯作者：
Kaemmerer, William F.
中科院分区：
文献类型：
--
作者：
Lombardi, Maria Stella;Jaspers, Leonie;Kaemmerer, William F.
使用RNA干扰来减少受影响大脑区域的亨廷顿蛋白(HTT)的表达，可能会为亨廷顿病(HD)提供有效的治疗，但目前尚不确定抑制杂合子患者的野生型和突变等位基因是否会带来更多的好处而不是伤害。先前的研究表明，使用针对HD mRNA包含单核苷酸多态(SNPs)的区域的siRNA可以仅抑制突变的等位基因。为了确定是否有超过少数的患者有资格接受等位基因特异性治疗，我们对327名无关的欧洲高加索人HD患者的HD基因的26个SNP位点的DNA进行了基因分型。超过86%的患者被发现在测试中至少有一个SNP是杂合子。因为这些位点是遗传相关的，所以不能使用单个SNPs的杂合率来预测需要多少个位点(以及相应的等位基因特异性siRNA)才能为这一比例的患者提供至少一种治疗可能性。通过计算所有组合，我们发现对应于七个位点的等位基因特异性siRNA库可以为85.6%的样本提供至少一个等位基因特异性siRNA治疗选项。此外，我们提供的证据表明，利用高通量筛选方法可以很容易地识别针对这些位点的等位基因特异性siRNA，并且使用该方法鉴定的等位基因特异性siRNA确实显示出选择性地抑制HD患者成纤维细胞中内源性突变的HTT蛋白。因此，等位基因特异的siRNA并不罕见，以至于难以发现并在治疗上使用。(C)2009 Elsevier Inc.保留所有权利。
Use of RNA interference to reduce huntingtin protein (htt) expression in affected brain regions may provide an effective treatment for Huntington disease (HD), but it remains uncertain whether suppression of both wild-type and mutant alleles in a heterozygous patient will provide more benefit than harm. Previous research has shown suppression of just the mutant allele is achievable using siRNA targeted to regions of HD mRNA containing single nucleotide polymorphisms (SNPs). To determine whether more than a minority of patients may be eligible for an allele-specific therapy, we genotyped DNA from 327 unrelated European Caucasian HD patients at 26 SNP sites in the HD gene. Over 86% of the patients were found to be heterozygous for at least one SNP among those tested. Because the sites are genetically linked, one cannot use the heterozygosity rates of the individual SNPs to predict how many sites (and corresponding allele-specific siRNA) would be needed to provide at least one treatment possibility for this percentage of patients. By computing all combinations, we found that a repertoire of allele-specific siRNA corresponding to seven sites can provide at least one allele-specific siRNA treatment option for 85.6% of our sample. Moreover, we provide evidence that allele-specific siRNA targeting these sites are readily identifiable using a high throughput screening method, and that allele-specific siRNA identified using this method indeed show selective suppression of endogenous mutant htt protein in fibroblast cells from HD patients. Therefore, allele-specific siRNA are not so rare as to be impractical to find and use therapeutically. (C) 2009 Elsevier Inc. All rights reserved.