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- Title
Increased efficacy of VX-809 in different cellular systems results from an early stabilization effect of F508del- CFTR.
- Authors
Farinha, Carlos M.; Sousa, Marisa; Canato, Sara; Schmidt, André; Uliyakina, Inna; Amaral, Margarida D.
- Abstract
Cystic fibrosis ( CF), the most common recessive autosomal disease among Caucasians, is caused by mutations in the gene encoding the CF transmembrane conductance regulator ( CFTR) protein. The most common mutation, F508del, leads to CFTR impaired plasma membrane trafficking. Therapies modulating CFTR basic defect are emerging, such as VX-809, a corrector of F508del- CFTR traffic which just succeeded in a Phase III clinical trial. We recently showed that VX-809 is additive to two other correctors ( VRT-325 and compound 4a). Here, we aimed to determine whether the differential rescuing by these compounds results from cell-specific factors or rather from distinct effects at the early biogenesis and/or processing. The rescuing efficiencies of the above three correctors were first compared in different cellular models (primary respiratory cells, cystic fibrosis bronchial epithelial and baby hamster kidney [ BHK] cell lines) by functional approaches: micro-Ussing chamber and iodide efflux. Next, biochemical methods (metabolic labeling, pulse-chase and immunoprecipitation) were used to determine their impact on CFTR biogenesis / processing. Functional analyses revealed that VX-809 has the greatest rescuing efficacy and that the relative efficiencies of the three compounds are essentially maintained in all three cellular models tested. Nevertheless, biochemical data show that VX-809 significantly stabilizes F508del- CFTR immature form, an effect that is not observed for C3 nor C4. VX-809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX-809 increases the stability of F508del- CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue.
- Subjects
CYSTIC fibrosis; GENETIC disorders; CYSTIC fibrosis transmembrane conductance regulator; CELL membrane formation; IMMUNOPRECIPITATION
- Publication
Pharmacology Research & Perspectives, 2015, Vol 3, Issue 4, pn/a
- ISSN
2052-1707
- Publication type
Article
- DOI
10.1002/prp2.152