Weidner Julie, Kolosionek Ewa, Holmila Reetta, Ax Elisabeth, Garreau Marion, Gnerlich Felix, Olsson Henric, Czechtizky Werngard, Vollmer Stefan, Rydzik Anna M
Translational Science Experimental Medicine, Research & Early Development, Respiratory & Immunology, BioPharmaceutical R&D, AstraZeneca, 431 83 Mölndal, Sweden.
Bioscience COPD/IPF, Research & Early Development, Respiratory & Immunology, BioPharmaceutical R&D, AstraZeneca, 431 83 Mölndal, Sweden.
Mol Ther Nucleic Acids. 2023 Aug 18;33:898-907. doi: 10.1016/j.omtn.2023.08.014. eCollection 2023 Sep 12.
MicroRNAs are attractive therapeutic targets in many diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Among microRNA inhibitors antimiRs have been proven successful in lowering aberrant microRNA levels in the clinic. We present a set of antimiRs targeting miR-34a, which has been shown to be dysregulated in chronic lung diseases. The tool compounds were taken up by a bronchial epithelial cell line and primary human bronchial epithelial cells, followed by efficient knockdown of miR-34a. Similar results were observed in 3D differentiated primary human bronchial epithelial cells cultured at the air-liquid interface. Varying chemical properties of antimiRs had significant impact on cellular uptake and potency, resulting in effective tool compounds for use in lung-relevant cellular systems. This report demonstrates gymnotic antimiR uptake and activity in 3D epithelial cell culture after apical administration, mimicking inhalation conditions.
微小RNA是包括慢性阻塞性肺疾病和特发性肺纤维化在内的许多疾病中颇具吸引力的治疗靶点。在微小RNA抑制剂中，抗微小RNA已在临床上被证明能成功降低异常的微小RNA水平。我们展示了一组靶向miR-34a的抗微小RNA，miR-34a已被证明在慢性肺部疾病中表达失调。这些工具化合物被支气管上皮细胞系和原代人支气管上皮细胞摄取，随后有效敲低miR-34a。在气液界面培养的三维分化原代人支气管上皮细胞中也观察到了类似结果。抗微小RNA不同的化学性质对细胞摄取和效力有显著影响，从而产生了可用于肺相关细胞系统的有效工具化合物。本报告证明了在模拟吸入条件下经顶端给药后，裸抗微小RNA在三维上皮细胞培养中的摄取和活性。
