Alpha-1 Antitrypsin-A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator ( ) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and...

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Bibliographic Details
Published in:International journal of molecular sciences 2020-01, Vol.21 (3), p.836
Main Authors: Hunt, Alison M D, Glasgow, Arlene M A, Humphreys, Hilary, Greene, Catherine M
Format: Article
Language:English
Subjects:
Autosomal recessive inheritance
Bacteria
Bacterial infections
Cystic fibrosis
Cytokines
Elastase
Enzymes
Extracellular matrix
Genetic disorders
Hereditary diseases
Homeostasis
Immune system
Infections
Inflammation
Leukocytes (neutrophilic)
Lung diseases
Lungs
miRNA
mRNA
Mutation
Neutrophils
Non-coding RNA
Pathogens
Protease
Proteinase
Proteins
Review
Serine
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Summary:Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator ( ) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and chronic bacterial infections. The CF lung endures an excess of neutrophilic inflammation, and whilst neutrophil serine proteases are a crucial part of the innate host defence to infection, a surplus of neutrophil elastase (NE) is understood to create a net destructive effect. Alpha-1 antitrypsin (A1AT) is a key antiprotease in the control of NE protease activity but is ineffective in the CF lung due to the huge imbalance of NE levels. Therapeutic strategies to boost levels of protective antiproteases such as A1AT in the lung remain an attractive research strategy to limit the damage from excess protease activity. microRNAs are small non-coding RNA molecules that bind specific cognate sequences to inhibit expression of target mRNAs. The inhibition of miRNAs which target the (A1AT-encoding gene) mRNA represents a novel therapeutic approach for CF inflammation. This could involve the delivery of antagomirs that bind and sequester the target miRNA, or target site blockers that bind miRNA recognition elements within the target mRNA to prevent miRNA interaction. Therefore, miRNA targeted therapies offer an alternative strategy to drive endogenous A1AT production and thus supplement the antiprotease shield of the CF lung.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms21030836