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首页> 外文期刊>EBioMedicine >Measurements of Functional Responses in Human Primary Lung Cells as a Basis for Personalized Therapy for Cystic Fibrosis
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Measurements of Functional Responses in Human Primary Lung Cells as a Basis for Personalized Therapy for Cystic Fibrosis

机译：测量人原代肺细胞功能反应作为囊性纤维化个性化治疗的基础

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Background: The 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. Methods: The 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 (I"e"q"-"S"C"-"F"s"k"+"G"e"n) in perfused open-circuit Ussing chambers. Efficacy of corrector C18 was also assessed on A561E/A561E and F508del/F508del cells. Results: Our 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. Conclusions: CF 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.
机译：背景：治疗最常见的引起CF突变的囊性纤维化（CF）患者（F508del）的最佳研究药物是VX-809（lumacaftor），该药物最近与ivacaftor结合在III期临床试验中获得了成功。该校正子将F508del-CFTR从其异常的细胞内定位拯救到细胞表面，这是所有II类CFTR突变体共有的交通缺陷。我们的目标是在源自CF患者的原代人支气管上皮（HBE）细胞中测试lumacaftor在其他II类突变体中的功效。方法：通过测量福斯高林加可逆的染料木黄酮诱导的等效短促性腺激素，对非CF和CF F508del / F508del，A561E / A561E，N1303K / G542X，F508del / G542X和F508del / Y1092X基因型的非CF和CF患者原代HBE细胞的作用进行了研究灌注开路使用室中的电路电流（I“ e” q“-” S“ C”-“ F” s“ k” +“ G” e“ n）。校正器C18的功效也通过A561E / A561E和F508del / F508del细胞结果：我们的数据表明，A561E（同时存在于两个等位基因中）对卢马卡托治疗产生的阳性反应与原代HBE细胞中F508del的等效功效相似;卢马卡托对Y1092X产生积极影响，但对N1303K没有积极影响我们的数据还显示，只有一个拷贝的F508del-CFTR的细胞对VX-809的反应较小，而且，来自不同供体的F508del-纯合子细胞之间的lumacaftor反应也存在很大差异，化合物C18无法挽救A561E-CFTR，但不能在F508del-CFTR中，因此似乎具有不同的作用机理离子不同于lumacaftor。结论：患有A561E的CF患者（可能还有患有Y1029X的患者）可以从lumacaftor中受益。此外，此处使用的方法论证了离体方法如何将个性化疗法应用于CF和可能的其他呼吸系统疾病。

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