Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma.
Muc5ac
RNA-seq
Staramine
TheraSilence
chemokine
cytokine
gene expression
locked nucleic acid
Journal
Molecular therapy. Nucleic acids
ISSN: 2162-2531
Titre abrégé: Mol Ther Nucleic Acids
Pays: United States
ID NLM: 101581621
Informations de publication
Date de publication:
06 Mar 2020
06 Mar 2020
Historique:
received:
20
02
2019
revised:
16
10
2019
accepted:
09
12
2019
pubmed:
12
2
2020
medline:
12
2
2020
entrez:
12
2
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32044723
pii: S2162-2531(20)30017-2
doi: 10.1016/j.omtn.2019.12.033
pmc: PMC7013130
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1000-1014Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
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