Cystic fibrosis (CF) remains the most common life-shortening hereditary disease in white populations, with high morbidity and mortality related to chronic airway mucus obstruction, inflammation, infection, and progressive lung damage. In 1989, the discovery that CF is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene that encodes a cAMP-dependent anion channel vital for proper Cl- and HCO3- transport across epithelial surfaces provided a solid foundation for unraveling underlying disease mechanisms and the development of therapeutics targeting the basic defect in people with CF. In this review, we focus on recent advances in our understanding of the molecular defects caused by different classes of CFTR mutations, implications for pharmacological rescue of mutant CFTR, and insights into how CFTR dysfunction impairs key host defense mechanisms, such as mucociliary clearance and bacterial killing in CF airways. Furthermore, we review the path that led to the recent breakthrough in the development of highly effective CFTR-directed therapeutics, now applicable for up to 90% of people with CF who carry responsive CFTR mutations, including those with just a single copy of the most common F508del mutation. Finally, we discuss the remaining challenges and strategies to develop highly effective targeted therapies for all patients and the unprecedented potential of these novel therapies to transform CF from a fatal to a treatable chronic condition.
Keywords: CF pathogenesis; CFTR mutations; clinical trials; personalized medicine; targeted therapies.
Potentiators (specific therapies for class III and IV mutations) for cystic fibrosis.Cochrane Database Syst Rev. 2019 Jan 7;1(1):CD009841. doi: 10.1002/14651858.CD009841.pub3. Cochrane Database Syst Rev. 2019. PMID: 30616300 Free PMC article.
CFTR: cystic fibrosis and beyond.Eur Respir J. 2014 Oct;44(4):1042-54. doi: 10.1183/09031936.00228013. Epub 2014 Jun 12. Eur Respir J. 2014. PMID: 24925916
Pharmacotherapy of the ion transport defect in cystic fibrosis: role of purinergic receptor agonists and other potential therapeutics.Am J Respir Med. 2003;2(4):299-309. doi: 10.1007/BF03256658. Am J Respir Med. 2003. PMID: 14719996 Review.
Pharmacological Correction of Cystic Fibrosis: Molecular Mechanisms at the Plasma Membrane to Augment Mutant CFTR Function.Curr Drug Targets. 2016;17(11):1275-81. doi: 10.2174/1389450117666151209114343. Curr Drug Targets. 2016. PMID: 26648081 Review.
Correctors (specific therapies for class II CFTR mutations) for cystic fibrosis.Cochrane Database Syst Rev. 2018 Aug 2;8(8):CD010966. doi: 10.1002/14651858.CD010966.pub2. Cochrane Database Syst Rev. 2018. PMID: 30070364 Free PMC article. Review.
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