کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2121319 1085776 2015 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Measurements of Functional Responses in Human Primary Lung Cells as a Basis for Personalized Therapy for Cystic Fibrosis
ترجمه فارسی عنوان
اندازه گیری پاسخ های عملکردی در سلول های اولیه انسانی انسان به عنوان مبنایی برای درمان شخصی برای فیبروز کیستیک
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی تحقیقات سرطان
چکیده انگلیسی


• A561E and Y1092X CFTR mutations (but not N1303K) respond positively to lumacaftor treatment.
• One copy of F508del-CFTR responds less to lumacaftor than 2 copies and F508del-responses vary greatly.
• CF patients with A561E (and likely also those with Y1029X) can potentially benefit from lumacaftor.
• The methodology used here exemplifies how ex vivo approaches may apply personalized therapies to CF and possibly other respiratory diseases.

BackgroundThe best investigational drug to treat cystic fibrosis (CF) patients with the most common CF-causing mutation (F508del) is VX-809 (lumacaftor) which recently succeeded in Phase III clinical trial in combination with ivacaftor. This corrector rescues F508del-CFTR from its abnormal intracellular localization to the cell surface, a traffic defect shared by all Class II CFTR mutants. Our goal here is to test the efficacy of lumacaftor in other Class II mutants in primary human bronchial epithelial (HBE) cells derived from CF patients.MethodsThe effect of lumacaftor was investigated in primary HBE cells from non-CF and CF patients with F508del/F508del, A561E/A561E, N1303K/G542X, F508del/G542X and F508del/Y1092X genotypes by measurements of Forskolin plus Genistein-inducible equivalent short-circuit current (Ieq-SC-Fsk + Gen) in perfused open-circuit Ussing chambers. Efficacy of corrector C18 was also assessed on A561E/A561E and F508del/F508del cells.ResultsOur data indicate that A561E (when present in both alleles) responds positively to lumacaftor treatment at equivalent efficacy of F508del in primary HBE cells. Similarly, lumacaftor has a positive impact on Y1092X, but not on N1303K. Our data also show that cells with only one copy of F508del-CFTR respond less to VX-809. Moreover, there is great variability in lumacaftor responses among F508del-homozygous cells from different donors. Compound C18 failed to rescue A561E-CFTR but not in F508del-CFTR, thus plausibly it has a different mechanism of action distinct from lumacaftor.ConclusionsCF patients with A561E (and likely also those with Y1029X) can potentially benefit from lumacaftor. Moreover, the methodology used here exemplifies how ex vivo approaches may apply personalized therapies to CF and possibly other respiratory diseases.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: EBioMedicine - Volume 2, Issue 2, February 2015, Pages 147–153
نویسندگان
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