Hundreds of dominant-negative myosin mutations have been identified that lead to hypertrophic cardiomyopathy, and the biomechanical link between mutation and disease is heterogeneous across this patient population. To increase the therapeutic feasibility of treating this diverse genetic population, we investigated the ability of locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) to selectively knock down mutant myosin transcripts by targeting single-nucleotide polymorphisms (SNPs) that were found to be common in the myosin heavy chain 7 () gene. We identified three SNPs in and designed ASO libraries to selectively target either the reference or alternate sequence. We identified ASOs that selectively knocked down either the reference or alternate allele at all three SNP regions. We also show allele-selective knockdown in a mouse model that was humanized on one allele. These results suggest that SNP-targeting ASOs are a promising therapeutic modality for treating cardiac pathology.

中文翻译：

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使用反义寡核苷酸等位基因选择性敲低 MYH7


已发现数百种显性失活肌球蛋白突变可导致肥厚型心肌病，并且突变与疾病之间的生物力学联系在该患者群体中是异质的。为了提高治疗这种多样化遗传群体的可行性，我们研究了锁核酸（LNA）修饰的反义寡核苷酸（ASO）通过靶向单核苷酸多态性（SNP）选择性敲低突变肌球蛋白转录物的能力。常见于肌球蛋白重链7()基因。我们在其中识别了三个 SNP，并设计了 ASO 文库来选择性地靶向参考序列或替代序列。我们确定了 ASO 选择性地敲低所有三个 SNP 区域的参考或替代等位基因。我们还在一个等位基因人源化的小鼠模型中展示了等位基因选择性敲低。这些结果表明，针对 SNP 的 ASO 是治疗心脏病的一种有前途的治疗方式。