RESUMEN
BACKGROUND: The potentiator ivacaftor (VX-770) has been approved for therapy of 38 cystic fibrosis (CF) mutations (â¼10% of the patient population) associated with a gating defect of the CF transmembrane conductance regulator (CFTR). Despite the success of VX-770 treatment of patients carrying at least one allele of the most common gating mutation G551D-CFTR, some lung function decline and P. aeruginosa colonization persist. This study aims at identifying potentiator combinations that can considerably enhance the limited channel activity of a panel of CFTR gating mutants over monotherapy. METHODS: The functional response of 13 CFTR mutants to single potentiators or systematic potentiator combinations was determined in the human bronchial epithelial cell line CFBE41o- and a subset of them was confirmed in primary human nasal epithelia (HNE). RESULTS: In six out of thirteen CFTR missense mutants the fractional plasma membrane (PM) activity, a surrogate measure of CFTR channel gating, reached only â¼10-50% of WT channel activity upon VX-770 treatment, indicating incomplete gating correction. Combinatorial potentiator profiling and cluster analysis of mutant responses to 24 diverse investigational potentiators identified several compound pairs that improved the gating activity of R352Q-, S549R-, S549N-, G551D-, and G1244E-CFTR to â¼70-120% of the WT. Similarly, the potentiator combinations were able to confer WT-like function to G551D-CFTR in patient-derived human nasal epithelia. CONCLUSION: This study suggests that half of CF patients with missense mutations approved for VX-770 administration, could benefit from the development of dual potentiator therapy.
Asunto(s)
Aminofenoles/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística , Transporte Iónico , Mucosa Nasal , Piranos/farmacología , Pirazoles/farmacología , Quinolonas/farmacología , Células Cultivadas , Agonistas de los Canales de Cloruro/clasificación , Agonistas de los Canales de Cloruro/farmacología , Análisis por Conglomerados , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Humanos , Activación del Canal Iónico/genética , Transporte Iónico/efectos de los fármacos , Transporte Iónico/genética , Mutación Missense , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/metabolismo , Mucosa Nasal/patología , Medicina de Precisión/métodosAsunto(s)
Agonistas de los Canales de Cloruro , Ensayos de Uso Compasivo/métodos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística , Aprobación de Drogas/métodos , Agonistas de los Canales de Cloruro/clasificación , Agonistas de los Canales de Cloruro/farmacología , Ensayos Clínicos como Asunto , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Accesibilidad a los Servicios de Salud/organización & administración , Humanos , Mutación , Evaluación de NecesidadesRESUMEN
The European Cystic Fibrosis Society (ECFS) Basic Science Working Group (BSWG) organized a session on the topic "Activating Alternative Chloride Channels to Treat CF: Friends or Foes?", within the 16th ECFS Basic Science Conference gathering â¼200 researchers from CF Basic Science. The session was organized into two round tables, each chaired by Margarida Amaral (BioISI, University of Lisboa, Portugal) and Jeffrey Beekman (University Medical Centre Utrecht, Netherlands) as Chair and Vice-Chair of the BSWG, respectively. The purpose of this session was to bring attention of participants of the ECFS Basic Science Conference to alternative chloride channels as important therapeutic targets for CF which may treat all individuals with CF, independently of their CFTR genotype. The session had various speakers who had presented abstracts to the conference on this topic and discussants with different views. Here we try to convey the presentations as well as ideas that emerged during the discussion.
