Arthur Kmit1, Fernando Augusto Lima Marson2, Stéphanie Villa-Nova Pereira3, Adriana Mendes Vinagre4, Gabriela Silva Leite4, Maria Fátima Servidoni4, José Dirceu Ribeiro4, Antônio Fernando Ribeiro4, Carmen Sílvia Bertuzzo5, Margarida Duarte Amaral6. 1. Department of Medical Genetics and Genomic Medicine, Faculty of Medical Sciences, University of Campinas, Brazil; Department of Pediatrics, Faculty of Medical Sciences, University of Campinas, Brazil. Electronic address: arthurkmit@gmail.com. 2. Department of Medical Genetics and Genomic Medicine, Faculty of Medical Sciences, University of Campinas, Brazil; Department of Pediatrics, Faculty of Medical Sciences, University of Campinas, Brazil. Electronic address: fernandolimamarson@hotmail.com. 3. Department of Medical Genetics and Genomic Medicine, Faculty of Medical Sciences, University of Campinas, Brazil. 4. Department of Pediatrics, Faculty of Medical Sciences, University of Campinas, Brazil. 5. Department of Medical Genetics and Genomic Medicine, Faculty of Medical Sciences, University of Campinas, Brazil. Electronic address: bertuzzo@unicamp.br. 6. University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, Portugal. Electronic address: mdamaral@fc.ul.pt.
Abstract
BACKGROUND: We analyzed the CFTR response to VX-809/VX-770 drugs in conditionally reprogrammed cells (CRC) of human nasal epithelium (HNE) from F508del/F508del patients based on SNP rs7512462 in the Solute Carrier Family 26, Member 9 (SLC26A9; MIM: 608481) gene. METHODS: The Isc-eq measurements of primary nasal epithelial cells from F508del/F508del patients (n = 12) for CFTR function were performed in micro Ussing chambers and compared with non-CF controls (n = 2). Data were analyzed according to the rs7512462 genotype which were determined by real-time PCR. RESULTS: The CRC-HNE cells from F508del/F508del patients evidenced high variability in the basal levels of CFTR function. Also, the rs7512462*C allele showed an increased basal CFTR function and higher responses to VX-809 + VX-770. The rs7512462*CC + CT genotypes together evidenced CFTR function levels of 14.89% relatively to wt/wt (rs7512462*CT alone-15.29%) i.e., almost double of rs7512462*TT (7.13%). Furthermore, sweat [Cl-] and body mass index of patients also evidenced an association with the rs7512462 genotype. CONCLUSION: The CFTR function can be performed in F508del/F508del patient-derived CRC-HNEs and its function and responses to VX-809 + VX-770 combination as well as clinical data, are all associated with the rs7512462 variant, which partially sheds light on the generally inter-individual phenotypic variability and in personalized responses to CFTR modulator drugs.
BACKGROUND: We analyzed the CFTR response to VX-809/VX-770 drugs in conditionally reprogrammed cells (CRC) of human nasal epithelium (HNE) from F508del/F508delpatients based on SNP rs7512462 in the Solute Carrier Family 26, Member 9 (SLC26A9; MIM: 608481) gene. METHODS: The Isc-eq measurements of primary nasal epithelial cells from F508del/F508delpatients (n = 12) for CFTR function were performed in micro Ussing chambers and compared with non-CF controls (n = 2). Data were analyzed according to the rs7512462 genotype which were determined by real-time PCR. RESULTS: The CRC-HNE cells from F508del/F508delpatients evidenced high variability in the basal levels of CFTR function. Also, the rs7512462*C allele showed an increased basal CFTR function and higher responses to VX-809 + VX-770. The rs7512462*CC + CT genotypes together evidenced CFTR function levels of 14.89% relatively to wt/wt (rs7512462*CT alone-15.29%) i.e., almost double of rs7512462*TT (7.13%). Furthermore, sweat [Cl-] and body mass index of patients also evidenced an association with the rs7512462 genotype. CONCLUSION: The CFTR function can be performed in F508del/F508delpatient-derived CRC-HNEs and its function and responses to VX-809 + VX-770 combination as well as clinical data, are all associated with the rs7512462 variant, which partially sheds light on the generally inter-individual phenotypic variability and in personalized responses to CFTR modulator drugs.
Authors: Anh-Thu N Lam; Melis A Aksit; Briana Vecchio-Pagan; Celeste A Shelton; Derek L Osorio; Arianna F Anzmann; Loyal A Goff; David C Whitcomb; Scott M Blackman; Garry R Cutting Journal: J Clin Invest Date: 2020-01-02 Impact factor: 14.808
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