Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences and Center for Brain Integration Research, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan.
Section of Molecular Technology, Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
Nucleic Acids Res. 2019 Aug 22;47(14):7321-7332. doi: 10.1093/nar/gkz492.
AntimiR is an antisense oligonucleotide that has been developed to silence microRNA (miRNA) for the treatment of intractable diseases. Enhancement of its in vivo efficacy and improvement of its toxicity are highly desirable but remain challenging. We here design heteroduplex oligonucleotide (HDO)-antimiR as a new technology comprising an antimiR and its complementary RNA. HDO-antimiR binds targeted miRNA in vivo more efficiently by 12-fold than the parent single-stranded antimiR. HDO-antimiR also produced enhanced phenotypic effects in mice with upregulated expression of miRNA-targeting messenger RNAs. In addition, we demonstrated that the enhanced potency of HDO-antimiR was not explained by its bio-stability or delivery to the targeted cell, but reflected an improved intracellular potency. Our findings provide new insights into biology of miRNA silencing by double-stranded oligonucleotides and support the in vivo potential of this technology based on a new class of for the treatment of miRNA-related diseases.
抗 miRNA 是一种反义寡核苷酸，已被开发用于沉默 microRNA（miRNA）以治疗难治性疾病。提高其体内疗效和降低其毒性是非常理想的，但仍然具有挑战性。我们在这里设计了异源双链寡核苷酸（HDO）-抗 miRNA，作为一种新技术，包含一个抗 miRNA 和它的互补 RNA。HDO-抗 miRNA 在体内与靶向 miRNA 的结合效率比其亲本单链抗 miRNA 高 12 倍。HDO-抗 miRNA 还在 miRNA 靶向信使 RNA 表达上调的小鼠中产生了增强的表型效应。此外，我们证明 HDO-抗 miRNA 的增强效力不能用其生物稳定性或递送到靶细胞来解释，而是反映了其在细胞内的效力提高。我们的发现为双链寡核苷酸对 miRNA 沉默的生物学提供了新的见解，并基于一种新的用于治疗 miRNA 相关疾病的药物，支持该技术的体内潜力。
