The cystic fibrosis airway milieu enhances rescue of F508del in a pre-clinical model

SMM exposure enhances functional rescue of F508del. F508del/F508del HBE cultures were exposed for 24 h to vehicle or 5 µM VX-809 in combination with 30 µL mucosal PBS or SMM. a) Representative short-circuit currents (I_sc, µA·cm⁻²) recorded in Ussing chambers. b) Quantification of F508del-mediated responses to forskolin (Fsk, 10 µM)+VX-770 (1 µM) and CFTR_inh-172 (10 µM). Data are expressed as mean±sem. ^#: p<0.05 VX-809 versus vehicle; ^¶: p<0.05, SMM versus PBS; ⁺: p<0.05, SMM/VX-809 versus PBS/VX-809. n=4 F508del/F508del HBE culture codes, and experiments were performed in 3–4 replicates/code in 14 measurements. c) Compiled data from baseline, amiloride-sensitive, residual (amiloride-insensitive) and UTP-dependent Isc responses. d) Representative Western blot of immunoprecipitated CFTR and tubulin controls. e) Quantification of band B as % values normalised from band B values from control (vehicle- and PBS-treated CF HBE). Data are expressed as mean±sem. ⁺: p<0.05, SMM+VX-809 versus VX-809. n=4 F508del/F508del HBE culture codes. f) Quantification of band C as % values normalised from band C values from control (vehicle- and PBS-treated CF HBE). Data are expressed as mean±sem. ⁺: p<0.05, SMM+VX-809 versus VX-809. N=4 F508del/F508del HBE culture codes. g) CFTR mRNA levels, determined by RT-PCR. Data are expressed as fold change relative to TATA-box binding protein mRNA. n=3 F508del/F508del HBE culture codes.