The holy grail of cystic fibrosis research: pharmacological repair of the F508del-CFTR mutation.

Therapeutic strategies aimed at correcting the defect of the cystic fibrosis transmembrane conductance regulator (CFTR) (“CFTR-repair”) constitute a new avenue towards the treatment of patients affected by Cystic Fibrosis (CF), the most common lethal monogenic disease in Caucasians. CF is caused by mutations in the CFTR gene, which codes for a 1480 amino-acid protein normally functioning as a chloride channel at apical membrane from epithelial cells (1). In the CFTR gene, more than 1900 mutations, most of which are disease-relevant, have been identified and then categorized in six different classes according to their functional impact (2). The phenotypic consequences of such genotypes comprise insufficiency of the exocrine pancreas, increased electrolytes in sweat, male infertility and—most prevalent—a debilitating and eventually lethal inflammation/infection-triggered respiratory dysfunction. Mutation-specific approaches are focusing on the identification of small molecules capable of correcting the deficient subcellular trafficking of the CFTR protein (“correctors”: agents that ensure the expression of the mutated protein at the apical plasma membrane) or defective gating (“potentiators”: agents that reinstate the channel function of mutated CFTR proteins that are orthotopically expressed).