Abstract Trinucleotide repeats are responsible for many genetic diseases. Previous studies have shown that duplex RNAs (dsRNAs) can be used to target expression of a mutant repeat allele while leaving expression of the wild-type allele untouched, creating opportunities for allele-selective inhibition and better therapeutic outcomes. In contrast to successes with other genes, we report here that we cannot achieve allele-selective inhibition when targeting the expanded CAG repeat within Ataxin-1 (ATXN1), the cause of spinal cerebellar ataxia-1 (SCA1). The most likely explanation for this unfavorable outcome is that the mean CAG repeat number within wild-type ATXN1 is relatively high compared to other trinucleotide repeat diseases. Because the wild-type repeat number is high, it is likely that there is poor discrimination between the mutant and wild-type repeat and less opportunity for allele-selective inhibition across the entire spectrum of mutations found in SCA1 patients. Our data support the conclusion that the potential for multiple cooperative binding interactions is a critical factor governing allele-selective recognition of trinucleotide repeat genes by duplex RNAs. These results should be helpful in predicting which diseases and which patients are most likely to benefit from allele-selective targeting of expanded repeats.

中文翻译：

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使用寡核苷酸对三核苷酸重复序列进行等位基因选择性抑制的限制——靶向 ataxin-1 中的 CAG 重复

摘要 三核苷酸重复是导致许多遗传疾病的原因。先前的研究表明，双链 RNA (dsRNA) 可用于靶向突变重复等位基因的表达，同时不影响野生型等位基因的表达，为等位基因选择性抑制和更好的治疗效果创造机会。与其他基因的成功相比，我们在此报告说，当靶向 Ataxin-1 (ATXN1) 内的扩展 CAG 重复序列时，我们无法实现等位基因选择性抑制，这是脊髓小脑共济失调-1 (SCA1) 的原因。对这种不利结果的最可能解释是，与其他三核苷酸重复疾病相比，野生型 ATXN1 内的平均 CAG 重复数量相对较高。因为野生型重复数高，在 SCA1 患者中发现的整个突变谱中，突变体和野生型重复序列之间的区分可能很差，并且等位基因选择性抑制的机会较少。我们的数据支持以下结论：多重协同结合相互作用的潜力是控制双链 RNA 对三核苷酸重复基因的等位基因选择性识别的关键因素。这些结果应该有助于预测哪些疾病和哪些患者最有可能受益于扩增重复的等位基因选择性靶向。我们的数据支持以下结论：多重协同结合相互作用的潜力是控制双链 RNA 对三核苷酸重复基因的等位基因选择性识别的关键因素。这些结果应该有助于预测哪些疾病和哪些患者最有可能受益于扩增重复的等位基因选择性靶向。我们的数据支持以下结论：多重协同结合相互作用的潜力是控制双链 RNA 对三核苷酸重复基因的等位基因选择性识别的关键因素。这些结果应该有助于预测哪些疾病和哪些患者最有可能受益于扩增重复的等位基因选择性靶向。