Modulating the cystic fibrosis transmembrane regulator – breaking the basic defects

The defective allele responsible for cystic fibrosis (CF) is found in one in 19 people in Ireland. Historically, treatment of CF comprised ameliorating patient symptoms, but recently there has been much progress in CF therapy, not least of which are the CFTR gene modulators. These target specific basic defects in the disease: that of deficient or abnormal synthesis; and, processing of the CFTR channel, thus treating the disease, for the first time, systemically. These compounds have implications for targeted CF therapy and mark a large step forward in the field. So far, three targets have been overcome, with varying degrees of success. There are six mutation classes in CF; Class I is most severe, but patient presentation depends on the specific combination of alleles. Kalydeco was developed for the class III G551D mutation, and demonstrated efficacy in homozygous patients, but the high cost of the drug remains an issue. Lumacaftor and VX-661 were developed to address the ΔF508 Class II mutation; lumacaftor was effective when used in conjunction with Kalydeco, and VX-661 is as yet undergoing trials. Lastly, investigations are ongoing to assess Ataluren as a modulator of the effects of the premature termination codons caused by Class I CF mutations; two of three phase II studies showed varied improvement in patient symptoms following treatment with Ataluren and a phase III trial is currently underway. This article discusses the progress in CF-modulating therapy hitherto.