MicroRNA (miRNA) inhibition is a promising therapeutic strategy in several disease indications. MRG-110 is a locked nucleic acid-based antisense oligonucleotide that targets miR-92a-3p and experimentally was shown to have documented therapeutic effects on cardiovascular disease and wound healing. To gain first insights into the activity of anti-miR-92a in humans, we investigated miR-92a-3p expression in several blood compartments and assessed the effect of MRG-110 on target derepression. Healthy adults were randomly assigned (5:2) to receive a single intravenous dose of MRG-110 or placebo in one of seven sequential ascending intravenous dose cohorts ranging from 0.01 to 1.5 mg/kg body weight. MiR-92a-3p whole blood levels were time and dose dependently decreased with half-maximal inhibition of 0.27 and 0.31 mg/kg at 24 and 72 h after dosing, respectively. In the high-dose groups, >95% inhibition was detected at 24–72 h postinfusion and significant inhibition was observed for 2 weeks. Similar inhibitory effects were detected in isolated CD31⁺ cells, and miR-92a-3p expression was also inhibited in extracellular vesicles in the high-dose group. Target derepression was measured in whole blood and showed that ITGA5 and CD93 were increased at a dose of 1.5 mg/kg. Single-cell RNA sequencing of peripheral blood cells revealed a cell type-specific derepression of miR-92a targets. Together this study demonstrates that systemic infusion of anti-miR-92a efficiently inhibits miR-92a in the peripheral blood compartment and derepresses miR-92a targets in humans.

中文翻译：

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Anti-miR-92a 的效率和靶向去抑制：人类研究中的首次结果。

MicroRNA (miRNA) 抑制是几种疾病适应症的有前途的治疗策略。MRG-110 是一种基于锁定核酸的反义寡核苷酸，其靶向 miR-92a-3p 并在实验中证明对心血管疾病和伤口愈合具有治疗作用。为了首先了解人类抗 miR-92a 的活性，我们研究了几个血液隔室中的 miR-92a-3p 表达，并评估了 MRG-110 对靶标去抑制的影响。健康成人被随机分配 (5:2)，在 0.01 至 1.5 mg/kg 体重范围内的七个连续递增静脉注射剂量组之一中接受单次静脉注射 MRG-110 或安慰剂。MiR-92a-3p 全血水平随时间和剂量依赖性降低，给药后 24 和 72 小时的半数最大抑制为 0.27 和 0.31 mg/kg，分别。在高剂量组中，在输注后 24-72 小时检测到 >95% 的抑制，并在 2 周内观察到显着的抑制。在分离的 CD31 中检测到类似的抑制作用⁺细胞和高剂量组的细胞外囊泡中 miR-92a-3p 的表达也受到抑制。在全血中测量了靶标去抑制，结果表明ITGA5和CD93在 1.5 mg/kg 的剂量下增加。外周血细胞的单细胞 RNA 测序揭示了 miR-92a 靶标的细胞类型特异性去抑制。该研究共同表明，全身输注抗 miR-92a 可有效抑制外周血区室中的 miR-92a，并解除人类中的 miR-92a 靶标。