Predicting CFTR activity with front-runner cystic fibrosis drugs

The past two decades have seen most research efforts targeted at correcting the ion transport deficiency of cystic fibrosis (CF), highlighting the required promotion and development of new drugs to tackle CF (Becq et al., 2011; Boyle and De Boeck, 2013; Riordan, 2008). The polyexocrinopathy genetic disease CF is caused by one of the 2000 documented mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR, OMIM #602421) among them the deletion F508 (F508del-CFTR) is the most common and severe CF mutation (Boyle and De Boeck, 2013; Riordan, 2008). F508del causes CFTR misfolding/ instability leading to defective protein biosynthesis, reduced plasma membrane residence and altered channel gating (Riordan, 2008; Becq, 2010). Whereas it remains unclear whether current small molecules targeting F508del-CFTRwill have therapeutic benefit, thewind is nevertheless changing for CF patients who are still awaiting a curative treatment. Indeed, new medications with orphan drug status are, for some, rapidly progressing in clinical trials (Becq et al., 2011), among them the F508del-CFTR corrector lumacaftor (VX-809) (Van Goor et al., 2011). Acceleration of drug development has been clearly encouraged by the recent successful marketing of Kalydeco®, the first personalized medication for CF patients directly targeting mutated CFTR proteins (Ramsey et al., 2011). The CFmutations can be classified into six classes (Welsh and Smith, 1993) helping research to being directed toward mutation-specific therapeutic agents. The most severe cases of CF belong to classes I, II and III, where little or no cAMP-dependent CFTR-mediated chloride ion transport is observed in epithelia expressing CFTR mutants. Mutations that have not been fully analyzed yet will be characterized as mutations of unknown clinical significance. Despite the fact that F508delCFTR is the main target for drug development in CF (Becq et al., 2011), categorizing about 2000 individual mutations identified so far in patients worldwide would be a tough job while still remaining an important challenge. It is also necessary to understand whether the mutation themselves can cause CF or not, or a CF-related disease (e.g., congenital bilateral absence of the vas deferens or CBAVD, or pancreatitis). For CF patients with a heterozygous genotype, it is also important to understand whether carrying a CF-causing mutation actually results in CF or not. In theory, the goal for such a classification is to predict the phenotype of a CF patient according to his/her genotype, but in practice this critically depends on our ability to functionally characterize the mutant CFTR. But, not all the CF mutations have been classified so far because