Increased efficacy of VX‐809 in different cellular systems results from an early stabilization effect of F508del‐CFTR

• DOI: 10.1002/prp2.152
• Publication Date: 2015-07-07T07:50:22Z
• Authors: Carlos M. Farinha; Marisa Sousa; Sara Canato; André Schmidt; Inna Uliyakina; Margarida D. Amaral
• Keywords: Potentiator

Abstract Cystic fibrosis ( CF ), the most common recessive autosomal disease among Caucasians, is caused by mutations in gene encoding transmembrane conductance regulator CFTR ) protein. The mutation, F508del, leads to impaired plasma membrane trafficking. Therapies modulating basic defect are emerging, such as VX ‐809, a corrector of F508del‐ traffic which just succeeded Phase III clinical trial. We recently showed that ‐809 additive two other correctors VRT ‐325 and compound 4a). Here, we aimed determine whether differential rescuing these compounds results from cell‐specific factors or rather distinct effects at early biogenesis and/or processing. efficiencies above three were first compared different cellular models (primary respiratory cells, cystic bronchial epithelial baby hamster kidney [ BHK ] cell lines) functional approaches: micro‐Ussing chamber iodide efflux. Next, biochemical methods (metabolic labeling, pulse‐chase immunoprecipitation) used their impact on / Functional analyses revealed has greatest efficacy relative essentially maintained all tested. Nevertheless, data show significantly stabilizes immature form, an effect not observed for C3 nor C4. also increase accumulation . Our suggest increases stability form phase its biogenesis, thus explaining increased when inducing rescue.