A variety of diseases are caused by deficiencies in amounts or activity of key proteins. An approach that increases the amount of a specific protein might be of therapeutic benefit. We reasoned that translation could be specifically enhanced using trans-acting agents that counter the function of negative regulatory elements present in the 5′ UTRs of some mRNAs. We recently showed that translation can be enhanced by antisense oligonucleotides (ASOs) that target upstream open reading frames. Here we report the amount of a protein can also be selectively increased using ASOs designed to hybridize to other translation inhibitory elements in 5′ UTRs. Levels of human RNASEH1, LDLR, and ACP1 and of mouse ACP1 and ARF1 were increased up to 2.7-fold in different cell types and species upon treatment with chemically modified ASOs targeting 5′ UTR inhibitory regions in the mRNAs encoding these proteins. The activities of ASOs in enhancing translation were sequence and position dependent and required helicase activity. The ASOs appear to improve the recruitment of translation initiation factors to the target mRNA. Importantly, ASOs targeting ACP1 mRNA significantly increased the level of ACP1 protein in mice, suggesting that this approach has therapeutic and research potentials.

中文翻译：

---

在5'UTR中靶向翻译抑制元件的反义寡核苷酸可以选择性增加蛋白质水平

各种疾病是由关键蛋白质的数量或活性不足引起的。增加特定蛋白质量的方法可能具有治疗益处。我们认为可以使用trans来特别增强翻译-作用剂，可抵消某些mRNA 5'UTR中存在的负调控元件的功能。我们最近显示，可通过靶向上游开放阅读框的反义寡核苷酸（ASO）来增强翻译。在这里，我们报道蛋白质的量也可以使用被设计为与5'UTRs中其他翻译抑制元件杂交的ASO选择性地增加。使用化学修饰的ASO靶向编码这些蛋白的mRNA中5'UTR抑制区后，在不同的细胞类型和物种中，人RNASEH1，LDLR和ACP1以及小鼠ACP1和ARF1的水平增加了2.7倍。ASO在增强翻译中的活性取决于序列和位置，并且需要解旋酶活性。ASO似乎可以改善翻译起始因子向目标mRNA的募集。重要的是，ASO定位ACP1 mRNA显着增加了小鼠中ACP1蛋白的水平，表明该方法具有治疗和研究潜力。