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Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2020-01-14 , DOI: 10.1016/j.omtn.2019.12.033 Sabrina C Ramelli 1 , Brian S Comer 1 , Jared M McLendon 1 , Lydia L Sandy 1 , Andrew P Ferretti 2 , Robert Barrington 2 , Jeff Sparks 3 , Majed Matar 3 , Jason Fewell 3 , William T Gerthoffer 4
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2020-01-14 , DOI: 10.1016/j.omtn.2019.12.033 Sabrina C Ramelli 1 , Brian S Comer 1 , Jared M McLendon 1 , Lydia L Sandy 1 , Andrew P Ferretti 2 , Robert Barrington 2 , Jeff Sparks 3 , Majed Matar 3 , Jason Fewell 3 , William T Gerthoffer 4
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To address the problem of poor asthma control due to drug resistance, an antisense oligonucleotide complementary to mmu-miR-145a-5p (antimiR-145) was tested in a house dust mite mouse model of mild/moderate asthma. miR-145 was targeted to reduce inflammation, regulate epithelial-mesenchymal transitions, and promote differentiation of structural cells. In addition, several chemical variations of a nontargeting oligonucleotide were tested to define sequence-dependent effects of the miRNA antagonist. After intravenous administration, oligonucleotides complexed with a pegylated cationic lipid nanoparticle distributed to most cells in the lung parenchyma but were not present in smooth muscle or the mucosal epithelium of the upper airways. Treatment with antimiR-145 and a nontargeting oligonucleotide both reduced eosinophilia, reduced obstructive airway remodeling, reduced mucosal metaplasia, and reduced CD68 immunoreactivity. Poly(A) RNA-seq verified that antimiR-145 increased levels of many miR-145 target transcripts. Genes upregulated in human asthma and the mouse model of asthma were downregulated by oligonucleotide treatments. However, both oligonucleotides significantly upregulated many genes of interferon signaling pathways. These results establish effective lung delivery and efficacy of locked nucleic acid/DNA oligonucleotides administered intravenously, and suggest that some of the beneficial effects of oligonucleotide therapy of lung inflammation may be due to normalization of interferon response pathways.
中文翻译：
抗炎 LNA 寡核苷酸的纳米颗粒递送可预防 HDM 哮喘模型中的气道炎症
为了解决由于耐药性导致哮喘控制不佳的问题，在轻度/中度哮喘的房尘螨小鼠模型中测试了与 mmu-miR-145a-5p (antimiR-145) 互补的反义寡核苷酸。 miR-145 的目标是减少炎症、调节上皮间质转化并促进结构细胞的分化。此外，还测试了非靶向寡核苷酸的几种化学变异，以确定 miRNA 拮抗剂的序列依赖性效应。静脉内给药后，与聚乙二醇化阳离子脂质纳米颗粒复合的寡核苷酸分布到肺实质中的大多数细胞，但不存在于平滑肌或上呼吸道粘膜上皮中。使用 antimiR-145 和非靶向寡核苷酸治疗均可减少嗜酸性粒细胞增多、减少阻塞性气道重塑、减少粘膜化生并减少 CD68 免疫反应性。 Poly(A) RNA-seq 证实 antimiR-145 增加了许多 miR-145 靶转录物的水平。寡核苷酸治疗可下调人类哮喘和小鼠哮喘模型中上调的基因。然而，这两种寡核苷酸均显着上调干扰素信号通路的许多基因。这些结果确立了静脉内施用的锁核酸/DNA寡核苷酸的有效肺部递送和功效，并表明寡核苷酸治疗肺部炎症的一些有益效果可能是由于干扰素反应途径的正常化。
更新日期：2020-01-14
中文翻译：
抗炎 LNA 寡核苷酸的纳米颗粒递送可预防 HDM 哮喘模型中的气道炎症
为了解决由于耐药性导致哮喘控制不佳的问题，在轻度/中度哮喘的房尘螨小鼠模型中测试了与 mmu-miR-145a-5p (antimiR-145) 互补的反义寡核苷酸。 miR-145 的目标是减少炎症、调节上皮间质转化并促进结构细胞的分化。此外，还测试了非靶向寡核苷酸的几种化学变异，以确定 miRNA 拮抗剂的序列依赖性效应。静脉内给药后，与聚乙二醇化阳离子脂质纳米颗粒复合的寡核苷酸分布到肺实质中的大多数细胞，但不存在于平滑肌或上呼吸道粘膜上皮中。使用 antimiR-145 和非靶向寡核苷酸治疗均可减少嗜酸性粒细胞增多、减少阻塞性气道重塑、减少粘膜化生并减少 CD68 免疫反应性。 Poly(A) RNA-seq 证实 antimiR-145 增加了许多 miR-145 靶转录物的水平。寡核苷酸治疗可下调人类哮喘和小鼠哮喘模型中上调的基因。然而，这两种寡核苷酸均显着上调干扰素信号通路的许多基因。这些结果确立了静脉内施用的锁核酸/DNA寡核苷酸的有效肺部递送和功效，并表明寡核苷酸治疗肺部炎症的一些有益效果可能是由于干扰素反应途径的正常化。
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