Cystic Fibrosis Transmembrane Conductance Regulator Modulators: The End of the Beginning

Abstract

Cystic fibrosis (CF) represents one of the success stories of modern medicine with sustained incremental increases in the survival from one of childhood death to one of adult survival into the middle decades over the past 30 years. Improving survival has focused on multidisciplinary management centered on treating the consequences of this genetic disease. It has been firmly established for more than 20 years that mutations in the CF transmembrane conductance regulator (CFTR) gene result in a defective protein that normally functions as a chloride channel on epithelial cell surfaces. Until recently, modulating CFTR dysfunction was only a research aspiration, however, greater focus placed upon addressing the primary defect of CF has developed several clinical therapeutic strategies in this area. This review highlights the evidence to date on efforts to modulate CFTR and restore robust functional protein to the cell surface. This approach has now led to the licensing of one CFTR potentiator, which has been shown to have significant clinical improvements in a subset of CF patients. This success represents the beginning for CFTR modulation and further research is ongoing which aims to broaden the applicability of these techniques.

Synergistic Potentiation of Cystic Fibrosis Transmembrane Conductance Regulator Gating by Two Chemically Distinct Potentiators, Ivacaftor (VX-770) and 5-Nitro-2-(3-Phenylpropylamino) Benzoate

“…Among the plethora of CFTR potentiators (Rowe and Verkman, 2013;Barry et al, 2015) that may serve as candidates to complement or supplant VX-770, the arylaminobenzoate 5-nitro-2-(3-phenylpropylamino) benzoate or 5-nitro-2-(3-phenylpropylamino) benzoate (NPPB) (Wang et al, 2005), which has long been known to the anion transport community as a chloride channel blocker (Wangemann et al, 1986), is particularly appealing. The action of NPPB is distinct from that of many other dual-action potentiators that increase the activity of CFTR at low concentrations but inhibit CFTR channel gating at high concentrations (Wang et al, 1998;Lansdell et al, 2000), as NPPB, when used at micromolar concentrations, potentiates CFTR channel gating as well as blocking the pore.…”

Moduladores CFTR (cystic fibrosis transmembrane conductance regulator): presente y futuro en la terapia de fibrosis quística. Revisión

“…De estas, la más común es la mutación G542X. [2][3][4] • Mutación clase II: Es un defecto cuantitativo, con producción de una proteína con mal plegamiento, que no alcanza la superficie al sufrir degradación intracelular. La mutación F508 es la más representativa de esta clase.…”

“…La mutación F508 es la más representativa de esta clase. [2][3][4] • Mutación clase III: Es un defecto cualitativo.…”

“…La mutación G551D es la más común de este tipo. [2][3][4] • Mutación clase IV: Defecto cualitativo con una proteína correctamente localizada, pero con un error en la conductancia. R117H es la más común.…”

“…R117H es la más común. [2][3][4] • Mutación clase V: Se muestra con una cantidad reducida de CFTR en la membrana. [2][3][4] • Mutación clase VI: Aumento del recambio de CFTR funcionales en la membrana.…”