**7. Conclusion**

targeting to the cell membrane. The correctors lumacaftor (VX 809) or VX 661 are designed to promote increased quantities of ΔF508 CFTR at the cell membrane surface. VX 809 has shown good results *in vitro* but it is likely that adequate correction of ΔF508 CFTR will need multicompound drug therapy [147, 151]. The potentiator ivacaftor (VX 770) was originally devel‐

**Figure 6.** CFTR function in human epithelia. Panel (A) illustrates defective CFTR Cl- transport due to the *G551D* muta‐

Use of this therapy involved a well-designed randomized, double blind, placebo-controlled trial. The study subjects had at least one *G551D CFTR* mutation and were randomly assigned to ivacaftor 150 mg twice daily or placebo for 48 weeks. The treatment group showed a sustained improvement from baseline in FEV1 by 10% compared with the placebo group. They were also 55% less likely to suffer a pulmonary exacerbation compared with their placebo counter parts, had higher health scores, gained weight and normalization of their sweat chloride levels. These benefits were sustained for the duration of the trial and the frequency of adverse events in the two groups was equivocal [152]. A shortcoming of the use of ivacaftor is that only 2–3% of individuals with CF have the *G551D* mutation and research is currently underway to ascertain whether ivacaftor may be employed for other mutations. A multicentre, phase II trial on the use of the CFTR corrector lumacaftor together with the CFTR potentiator ivacaftor for the treatment of patients with CF with the *ΔF508 CFTR* mutation was performed. The primary outcome was change in sweat chloride concentration with combina‐ tion therapy in the *∆F508* subjects, however a minimal effect on sweat chloride level was observed [153]. It is postulated that the reason behind this was that the potentiator rendered the CFTR protein less stable and increased its removal from the cell membrane. However,

tion. Image (B) illustrates corrected function post VX-770 (ivacaftor) treatment.

oped to augment the activity and efficiency of the abnormal CFTR protein (Figure 6).

264 Cystic Fibrosis in the Light of New Research

A plethora of studies on neutrophil function in CF have been performed and demonstrate alterations in cellular activities including impaired microbial uptake [156, 157], defective intracellular kinase activation [116], cellular inactivation [158], and increased oxidant forma‐ tion [106, 159]. Furthermore, an additional area of intense research has focused on persistent mammalian target of rapamycin (mTOR) and cyclic AMP response element binding protein (CREB) pathway activation in CF airway neutrophils [160], with more recent data suggesting that neutrophils express augmented cell surface nutrient transporter expression and glucose uptake, consistent with metabolic adaptation [161]. As the CF neutrophil may shape the inflammatory response and influence patient outcome, further research investigating the CF neutrophil is required. In addition, a promising development in the treatment of airway inflammation involves the correction of CFTR dysfunction. If CFTR dysfunction is corrected at a very early age, it is possible that neutrophil induced inflammation involving impaired trafficking, delayed apoptosis, impaired degranulation, and bacterial killing may be signifi‐ cantly curtailed.
