Genotype-specific smallmolecule therapy for cystic fibrosis

The prognosis for patients with cystic fibrosis (CF) has improved greatly over the past 30 years but the median age of survival is still only to the patients late 30s. New treatments are required to decrease morbidity and improve mortality. The basic defect in CF lies in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, mutations of which lead to a dysfunctional CFTR protein. The way in which the protein is defective differs between the six so-called mutation classes. An understanding of these classes has led to the development of mutation-specific small-molecule treatments. Class I mutations are caused by the presence of a premature termination codon. Ataluren is a systemic agent that allows read-through of the mutated mRNA and translation of full-length protein. A phase III clinical trial has recently been completed. In class II mutations, the most common of which is Phe508del (previously termed DF508), the resulting CFTR protein is misfolded and is not trafficked through the cytoplasm to the cell membrane. CFTR-corrector drugs seek to facilitate such trafficking; recently increased understanding of the complex nature of the misfolding events may explain why this approach is, to date, rather difficult. Improvements in CFTR protein function have been achieved in vivo and clinical trial data are beginning to emerge. It may be necessary to use correctors with potentiators and combination trials of two correctors, VX-809 and VX-661, with or without the CFTR potentiator ivacaftor are underway. The latter was initially developed and tested in patients with the class III mutation Gly551Asp (previously termed G551D). In cells with this mutation, CFTR protein reaches the cell surface but fails to respond to cellular signals to open and conduct chloride. Ivacaftor increases the probability that the channel is open and has led to significant clinical benefit in patients with the Gly551Asp mutation; it is now being investigated in other class III and some class IV mutations. Ivacaftor is the first genotype-specific treatment to demonstrate clinical efficacy and to be approved for licence. Other compounds are currently in development and the field is optimistic that drugs for other genotypes will not be far behind.