Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma

Sabrina C. Ramelli; Brian S. Comer; Jared M. McLendon; Lydia L. Sandy; Andrew P. Ferretti; Robert Barrington; Jeff Sparks; Majed Matar; Jason Fewell; William T. Gerthoffer

doi:10.1016/j.omtn.2019.12.033

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Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma

Journal article

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Peer reviewed

Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma

Sabrina C. Ramelli, Brian S. Comer, Jared M. McLendon, Lydia L. Sandy, Andrew P. Ferretti, Robert Barrington, Jeff Sparks, Majed Matar, Jason Fewell and William T. Gerthoffer

Molecular therapy. Nucleic acids, Vol.19, pp.1000-1014

03/06/2020

DOI: 10.1016/j.omtn.2019.12.033

PMCID: PMC7013130

PMID: 32044723

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Abstract

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. [Display omitted]

chemokine

cytokine

gene expression

locked nucleic acid

Muc5ac

RNA-seq

Staramine

TheraSilence

Details

Title: Subtitle: Nanoparticle Delivery of Anti-inflammatory LNA Oligonucleotides Prevents Airway Inflammation in a HDM Model of Asthma
Creators: Sabrina C. Ramelli - University of South Alabama
Brian S. Comer - University of South Alabama
Jared M. McLendon - University of South Alabama
Lydia L. Sandy - University of South Alabama
Andrew P. Ferretti - University of South Alabama
Robert Barrington - University of South Alabama
Jeff Sparks - Celsion (United States)
Majed Matar - Celsion (United States)
Jason Fewell - Celsion (United States)
William T. Gerthoffer - University of South Alabama
Resource Type: Journal article
Publication Details: Molecular therapy. Nucleic acids, Vol.19, pp.1000-1014
DOI: 10.1016/j.omtn.2019.12.033
PMID: 32044723
PMCID: PMC7013130
NLM abbreviation: Mol Ther Nucleic Acids
ISSN: 2162-2531
eISSN: 2162-2531
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000002, name: NIH, award: HL077726, UL1TR001417, AI116985; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: GM103440
Language: English
Date published: 03/06/2020
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Internal Medicine
Record Identifier: 9984618507502771

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