“The journey of a thousand miles…”

T reatment of cystic fibrosis (CF) is in a state of transition. 25 yrs ago the emphasis was on the downstream consequences of the disease, the prevention (as far as possible) and treatment of airway infection and inflammation, malabsorption, diabetes, liver disease and the many complications , such as bone disease and subclinical insulin deficiency, that have emerged as longevity has increased. In 1989, the CF gene (CF transmembrane regulator; CFTR) was localised to the long arm of chromosome 7 [1–3] and confirmed to be a chloride ion transporter. This has stimulated an explosion of knowledge about the basic biology of CF. Amongst the many advances, the recognition [4] that there are different classes of mutations (table 1) has raised the possibility of genotype specific therapy, not merely for CF, but also for other genetic diseases. Perhaps in the future we will be asking not which gene locus is affected in a given patient, but which class of problem is the issue. Overriding premature stop codons (class 1 mutations) may potentially lead to an improvement in other respiratory diseases (e.g. primary ciliary dyskinesia) and non-respiratory conditions, such as Duchenne muscular dystrophy. We stand on the threshold of a new exciting age of treatments aimed at the basic molecular defect in CF, far upstream from the catastrophic consequences of CFTR dysfunction on end organs. However, clear-headed consideration is warranted amongst the excitement. Despite the brilliance of the scientific insights which have sprung up from the discovery of CFTR, .20 yrs later it is sobering to reflect that to date, no single CF patient has derived clinical benefit from these molecular discoveries. Thankfully, the speculation of the early 1990s, that gene therapy would cure CF within 5 yrs, has been replaced by more realistic prognostications. There are numerous promising candidates for genotype specific therapies (table 1), including gene therapy (which is of course potentially applicable irrespective of genotype), PTC 124 [5], vertex compounds (VX-809 and VX-770) [6, 7], and a whole array of other CFTR correctors (which increase CFTR trafficking to the cell membrane) and potentiators (which increase CFTR activity when it has reached the apical cell membrane) [6]. However, at the moment they are just that, promising candidates, which have shown proof of concept biological activity in cellular, animal and some short-term human studies, but, as yet, no medium-term therapeutic benefit. The most common CFTR mutation in white races is DF …