Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA
Biology Department, Lewis University, Romeoville, Illinois 60446, USA.
RNA. 2024 Nov 18;30(12):1543-1553. doi: 10.1261/rna.080021.124.
MicroRNAs (miRNAs) are regulators of gene expression, and their dysregulation is linked to cancer and other diseases, making them important therapeutic targets. Several strategies for targeting and modulating miRNA activity are being explored. For example, steric-blocking antisense oligonucleotides (ASOs) can reduce miRNA activity by either blocking binding sites on specific mRNAs or base-pairing to the miRNA itself to prevent its interaction with the target mRNAs. ASOs have been less explored as a tool to elevate miRNA levels, which could also be beneficial for treating disease. In this study, using the /miR-1225 gene locus as an example, where miR-1225 is located within a intron, we demonstrate an ASO-based strategy that increases miRNA abundance by enhancing biogenesis from the primary miRNA transcript. Disruptions in and miR-1225 are associated with autosomal dominant polycystic kidney disease (ADPKD) and various cancers, respectively, making them important therapeutic targets. We investigated sequence variants reported in ADPKD that are located within the sequence shared by miR-1225 and and identified one that causes a reduction in miR-1225 without affecting We show that this reduction in miR-1225 can be recovered by treatment with a steric-blocking ASO. The ASO-induced increase in miR-1225 correlates with a decrease in the abundance of predicted miR-1225 cellular mRNA targets. This study demonstrates that miRNA abundance can be elevated using ASOs targeted to the primary transcript. This steric-blocking ASO-based approach has broad potential application as a therapeutic strategy for diseases that could be treated by modulating miRNA biogenesis.
微小 RNA（miRNA）是基因表达的调控因子，其失调与癌症和其他疾病有关，使其成为重要的治疗靶点。目前正在探索几种靶向和调节 miRNA 活性的策略。例如，空间位阻反义寡核苷酸（ASO）可以通过以下方式降低 miRNA 的活性：要么阻断特定 mRNAs 上的结合位点，要么与 miRNA 本身碱基配对，以防止其与靶 mRNAs 相互作用。ASO 作为一种提高 miRNA 水平的工具的应用研究较少，而提高 miRNA 水平也可能有益于治疗疾病。在这项研究中，我们以 miR-1225 基因座为例，miR-1225 位于一个内含子中，展示了一种基于 ASO 的策略，通过增强初级 miRNA 转录物的生物发生来增加 miRNA 的丰度。 和 miR-1225 的破坏分别与常染色体显性多囊肾病（ADPKD）和各种癌症相关，使其成为重要的治疗靶点。我们研究了位于 miR-1225 和 共享序列中的 ADPKD 中报道的 序列变异体，并鉴定出一个导致 miR-1225 减少而不影响 的变异体。我们表明，用空间位阻 ASO 处理可以恢复这种 miR-1225 的减少。ASO 诱导的 miR-1225 增加与预测的 miR-1225 细胞 mRNA 靶标丰度的降低相关。这项研究表明，使用靶向初级转录物的 ASO 可以提高 miRNA 的丰度。这种基于空间位阻 ASO 的方法具有广泛的潜在应用，可作为通过调节 miRNA 生物发生治疗疾病的治疗策略。
