Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) 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 SERPINA1 (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.
Highlights
Cystic fibrosis (CF) is a complex inherited disorder that affects numerous organ systems, principally the respiratory and gastro-intestinal tracts [1]. It is inherited in an autosomal recessive manner, where individuals that are heterozygous for a mutant cystic fibrosis transmembrane conductance regulator allele (CFTR) are termed carriers of the disease and are largely asymptomatic; whereas those who carry two mutant CFTR alleles have the disease
In vivo experiments showcased a significant and widespread decrease in Z-Alpha-1 antitrypsin (A1AT) accumulation within hepatocytes [110]. These findings suggest that dual microRNA and rAVV therapy has the potential to halt the progression of A1AT deficiency (A1ATD)-mediated liver disease
As CF lung disease is so dominantly characterised by neutrophilic inflammation, the neutrophil serine protease neutrophil elastase (NE) is present at vastly excessive levels
Summary
Cystic fibrosis (CF) is a complex inherited disorder that affects numerous organ systems, principally the respiratory and gastro-intestinal tracts [1]. It is inherited in an autosomal recessive manner, where individuals that are heterozygous for a mutant cystic fibrosis transmembrane conductance regulator allele (CFTR) are termed carriers of the disease and are largely asymptomatic; whereas those who carry two mutant CFTR alleles have the disease. CF is the most common inherited lethal disorder in the Western population, with up to 30,000 individuals in the United States and 27,000 in Europe having the disease [2]
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