Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis

Abstract

Purpose of review: Recent progress in understanding the production, processing, and function of the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator (CFTR), has revealed new therapeutic targets to repair the mutant protein. Classification of CFTR mutations and new treatment strategies to address each will be described here.

Recent findings: High-throughput screening and other drug discovery efforts have identified small molecules that restore activity to mutant CFTR. Compounds such as VX-770 that potentiate CFTR have demonstrated exciting results in recent clinical trials and demonstrate robust effects across several CFTR mutation classes in the laboratory. A number of novel F508del CFTR processing correctors restore protein to the cell surface and improve ion channel function in vitro and are augmented by coadministration of CFTR potentiators. Ongoing discovery efforts that target protein folding, CFTR trafficking, and cell stress have also indicated promising results. Aminoglycosides and the novel small molecule ataluren induce translational readthrough of nonsense mutations in CFTR and other genetic diseases in vitro and in vivo and have shown activity in proof of concept trials, and ataluren is now being studied in confirmatory trials.

Summary: An improved understanding of the molecular mechanisms underlying the basic genetic defect in cystic fibrosis have led to new treatment strategies to repair the mutant protein.

Figure 1. Therapeutic approaches to address various cystic fibrosis transmembrane conductance regulator mutation classes

Classes of defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene include PTCs causing truncated protein translation (class I); misfolded CFTR, including deletion of phenylalanine at position 508 (class II); full-length CFTR that reaches the cell surface, but exhibits abnormal channel gating (class III) or reduced pore conductivity (class IV); CFTR with splicing errors that reduce surface expression (class V); and C-terminus mutations (class VI) that reduce membrane residence time. PTC suppressors (e.g. aminoglycosides and ataluren) bind to ribosomal subunits (green star) to allow suppression of PTCs and expression of full-length protein. Class II mutations like F508del can respond to small-molecule corrector compounds to restore folding defects and/or enhance expression of the channel at the cell membrane. Without correction, almost all F508del CFTR is shunted to the proteosome, leaving detectable surface protein in only select individuals. CFTR potentiators are currently in human clinical trials (VX-770, green chevron) for patients with G551D and F508del CFTR. Future directions include exploring the use of CFTR potentiators for other CFTR mutations known to reside at the cell surface. Combination therapy with potentiators has also been proposed for classes I and II CFTR mutations. PTC, premature termination codon.