依伐卡托对 CFTR 错义突变相关蛋白加工或功能缺陷的影响。
Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function.
机构信息
Vertex Pharmaceuticals Incorporated, 130 Waverly St, Cambridge, MA, United States; Vertex Pharmaceuticals Incorporated, 11010 Torreyana Road, San Diego, CA 92121, United States.
Vertex Pharmaceuticals Incorporated, 11010 Torreyana Road, San Diego, CA 92121, United States.
出版信息
J Cyst Fibros. 2014 Jan;13(1):29-36. doi: 10.1016/j.jcf.2013.06.008. Epub 2013 Jul 23.
BACKGROUND
Ivacaftor (KALYDECO™, VX-770) is a CFTR potentiator that increased CFTR channel activity and improved lung function in patients age 6 years and older with CF who have the G551D-CFTR gating mutation. The aim of this in vitro study was to evaluate the effect of ivacaftor on mutant CFTR protein forms with defects in protein processing and/or channel function.
METHODS
The effect of ivacaftor on CFTR function was tested in electrophysiological studies using a panel of Fischer rat thyroid (FRT) cells expressing 54 missense CFTR mutations that cause defects in the amount or function of CFTR at the cell surface.
RESULTS
Ivacaftor potentiated multiple mutant CFTR protein forms that produce functional CFTR at the cell surface. These included mutant CFTR forms with mild defects in CFTR processing or mild defects in CFTR channel conductance.
CONCLUSIONS
These in vitro data indicated that ivacaftor is a broad acting CFTR potentiator and could be used to help stratify patients with CF who have different CFTR genotypes for studies investigating the potential clinical benefit of ivacaftor.
背景
依伐卡托（KALYDECO™，VX-770）是一种 CFTR 增效剂，可增加 CFTR 通道活性，并改善 6 岁及以上患有 CF 的患者的肺功能，这些患者携带 G551D-CFTR 门控突变。本体外研究旨在评估依伐卡托对具有蛋白加工和/或通道功能缺陷的突变 CFTR 蛋白形式的影响。
方法
使用一组表达 54 种导致 CFTR 在细胞表面数量或功能缺陷的错义 CFTR 突变的 Fischer 大鼠甲状腺（FRT）细胞，在电生理学研究中测试依伐卡托对 CFTR 功能的影响。
结果
依伐卡托增强了多种产生功能性 CFTR 的突变 CFTR 蛋白形式。这些包括 CFTR 加工轻度缺陷或 CFTR 通道电导轻度缺陷的突变 CFTR 形式。
结论
这些体外数据表明，依伐卡托是一种广泛作用的 CFTR 增效剂，可用于帮助对具有不同 CFTR 基因型的 CF 患者进行分层，以研究依伐卡托的潜在临床获益。
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