囊性纤维化
囊性纤维化跨膜传导调节器
伊瓦卡夫托
医学
新生儿筛查
内科学
体外
药理学
内分泌学
分子生物学
生物
生物化学
儿科
作者
Hermann Bihler,Andrey Sivachenko,Linda Millen,Priyanka Bhatt,Amita Thakerar Patel,Justin Chin,Violaine Bailey,Isaac Musisi,André LaPan,Norm Allaire,J Conté,Noah Simon,Amalia Magaret,Karen S. Raraigh,Garry R. Cutting,William R. Skach,Robert J. Bridges,Philip Thomas,Martin Mense
标识
DOI:10.1016/j.jcf.2024.02.006
摘要
BackgroundIn 2017, the US Food and Drug Administration initiated expansion of drug labels for the treatment of cystic fibrosis (CF) to include CF transmembrane conductance regulator (CFTR) gene variants based on in vitro functional studies. This study aims to identify CFTR variants that result in increased chloride (Cl−) transport function by the CFTR protein after treatment with the CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA). These data may benefit people with CF (pwCF) who are not currently eligible for modulator therapies.MethodsPlasmid DNA encoding 655 CFTR variants and wild-type (WT) CFTR were transfected into Fisher Rat Thyroid cells that do not natively express CFTR. After 24 h of incubation with control or TEZ and ELX, and acute addition of IVA, CFTR function was assessed using the transepithelial current clamp conductance assay. Each variant's forskolin/cAMP-induced baseline Cl− transport activity, responsiveness to IVA alone, and responsiveness to the TEZ/ELX/IVA combination were measured in three different laboratories. Western blots were conducted to evaluate CFTR protein maturation and complement the functional data.Results and conclusions253 variants not currently approved for CFTR modulator therapy showed low baseline activity (<10 % of normal CFTR Cl− transport activity). For 152 of these variants, treatment with ELX/TEZ/IVA improved the Cl− transport activity by ≥10 % of normal CFTR function, which is suggestive of clinical benefit. ELX/TEZ/IVA increased CFTR function by ≥10 percentage points for an additional 140 unapproved variants with ≥10 % but <50 % of normal CFTR function at baseline. These findings significantly expand the number of rare CFTR variants for which ELX/TEZ/IVA treatment should result in clinical benefit.
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