Inhaled ENaC antisense oligonucleotide ameliorates cystic fibrosis-like lung disease in mice

被引：68

作者：

Crosby, Jeff R. ^{[1
]}

Zhao, Chenguang ^{[1
]}

Jiang, Chong ^{[2
]}

Bai, Dong ^{[1
]}

Katz, Melanie ^{[1
]}

Greenlee, Sarah ^{[1
]}

Kawabe, Hiroshi ^{[3
]}

McCaleb, Michael ^{[1
]}

Rotin, Daniela ^{[2
]}

Guo, Shuling ^{[1
]}

Monia, Brett P. ^{[1
]}

机构：

[1] Ionis Pharmaceut, 2855 Gazelle Court, Carlsbad, CA 92010 USA

[2] Hosp Sick Children, 686 Bay St, Toronto, ON M5G 0A4, Canada

[3] Max Planck Inst Expt Med, Gottingen, Germany

来源：

JOURNAL OF CYSTIC FIBROSIS | 2017年 / 16卷 / 06期

关键词：

Cystic fibrosis; ENaC; Antisense oligonucleotide; Aerosol; EPITHELIAL NA+ CHANNEL; SODIUM-CHANNELS; MOLECULAR-BASIS; ALLERGIC MICE; CFTR; INHALATION; AMILORIDE; MOUSE; GENE; IDENTIFICATION;

D O I：

10.1016/j.jcf.2017.05.003

中图分类号：

R56 [呼吸系及胸部疾病];

学科分类号：

摘要：

Background: Epithelial sodium channel (ENaC, Scnnl) hyperactivity in the lung leads to airway surface dehydration and mucus accumulation in cystic fibrosis (CF) patients and in mice with CF-like lung disease. Methods: We identified several potent ENaC specific antisense oligonucleotides (ASOs) and tested them by inhalation in mouse models of CF-like lung disease: Results: The inhaled ASOs distributed into lung airway epithelial cells and decreased ENaC expression by inducing RNase H1-dependent degradation of the targeted Scnnla mRNA. Aerosol delivered ENaC ASO down-regulated mucus marker expression and ameliorated goblet cell metaplasia, inflammation, and airway hyper-responsiveness. Lack of systemic activity of ASOs delivered via the aerosol route ensures the safety of this approach. Conclusions: Our results demonstrate that antisense inhibition of ENaC in airway epithelial cells could be an effective and safe approach for the prevention and reversal of lung symptoms in CF and potentially other inflammatory diseases of the lung. (c) 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

引用

页码：671 / 680

页数：10

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