• Marijke Proesmans, François Vermeulen, and Kris De Boeck.
• Department of Pediatrics, University Hospital of Leuven, Herestraat 49, 3000, Leuven, Belgium. marijke.proesmans@uzleuven.be
• Eur. J. Pediatr. 2008 Aug 1; 167 (8): 839-49.

AbstractChronic relentless lung infection and pancreatic insufficiency are the cardinal features of cystic fibrosis (CF), a life-shortening autosomal recessive disease. Mutations in the 'cystic fibrosis transmembrane conductance regulator' (CFTR) are currently classified into five groups according to their repercussion on CFTR protein synthesis and its chloride channel function. Stop codon mutations (class I) result in a truncated nonfunctional CFTR, class II mutations consist of aberrantly folded CFTR protein that is degraded by the cell quality control system, while class III mutations lead to defective regulation of the CFTR protein and, consequently, the absence of CFTR function. These three classes usually lead to a classic CF phenotype with pancreatic insufficiency. CFTR mutations that lead to defective chloride conductance are grouped together in class IV. Class V mutations interfere with normal transcription, thereby reducing the amount of otherwise normal CFTR. These latter two classes are mostly associated with a milder expression of the disease. In the absence of CFTR function, unrestrained Na+ absorption and the failure of active Cl- secretion lead to a decreased airway surface liquid (ASL) volume and subsequent failure of normal mucociliary clearance. This review highlights recent therapeutic strategies that either target the underlying defect or the early steps in CF pathophysiology. To date, gene therapy has failed to demonstrate a clinical benefit after repeated administration. Mutation-specific chloride channel correction pharmacotherapy is currently being developed, an example of which is PTC124, a new chemical compound that selectively induces read-through of premature stop codons. However, clinical efficacy for most of the compounds still has to be proven in large clinical trials. The positive effect of nebulised hypertonic saline on mucociliary clearance is based on the restoration of ASL height. Recent advances in the current treatment of lung infection and inflammation are highlighted in this review. Lung transplantation should be considered in terminally ill patients, but the timing of the transplantation is crucial: transplanting too early shortens survival, while transplanting too late results in patients dying on the waiting list.

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