Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators
Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators
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DOI：
10.1172/jci.insight.121159
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发表时间：
2018-07-16
期刊：
影响因子：
8
通讯作者：
Cutting, Garry R.
中科院分区：
文献类型：
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作者：
Han, Sangwoo T.;Rab, Andras;Cutting, Garry R.
囊性纤维化（CF）个体的治疗已经通过靶向CF跨膜传导调节因子（CFTR）中的选择致病性变体的小分子疗法而改变。为了扩大治疗资格，我们从人CF支气管上皮细胞（CFBE 41 o（-））基因组中的单个位点稳定表达了43种与中度CF相关的罕见错义CFTR变体。对于增效剂依伐卡托、校正剂鲁玛卡托和依伐卡托-鲁玛卡托联合治疗，药物反应的幅度与残余CFTR功能高度相关。在Fischer大鼠甲状腺（FRT）细胞中稳定表达的第二组16种变体的反应显示出几乎相同的相关性。鉴定了对特定治疗表现出统计学显著更高应答的变体亚组。此外，在CFBE细胞（43个中的40个）和FRT细胞（16个中的13个）中研究的几乎所有变体都表现出比单独的任一调节剂对依伐卡托-鲁玛卡托组合疗法更大的响应。总之，这些变体代表了CFTR 2数据库中至少有1个错义变体的87%的个体。因此，我们的研究结果表明，大多数携带错义变体的CF个体（a）可能对目前可用的调节剂治疗有适度的应答，而一小部分将具有显著的应答，以及（B）可能从联合治疗中获得最大的益处。
Treatment of individuals with cystic fibrosis (CF) has been transformed by small molecule therapies that target select pathogenic variants in the CF transmembrane conductance regulator (CFTR). To expand treatment eligibility, we stably expressed 43 rare missense CFTR variants associated with moderate CF from a single site in the genome of human CF bronchial epithelial (CFBE41o(-)) cells. The magnitude of drug response was highly correlated with residual CFTR function for the potentiator ivacaftor, the corrector lumacaftor, and ivacaftor-lumacaftor combination therapy. Response of a second set of 16 variants expressed stably in Fischer rat thyroid (FRT) cells showed nearly identical correlations. Subsets of variants were identified that demonstrated statistically significantly higher responses to specific treatments. Furthermore, nearly all variants studied in CFBE cells (40 of 43) and FRT cells (13 of 16) demonstrated greater response to ivacaftor-lumacaftor combination therapy than either modulator alone. Together, these variants represent 87% of individuals in the CFTR2 database with at least 1 missense variant. Thus, our results indicate that most individuals with CF carrying missense variants are (a) likely to respond modestly to currently available modulator therapy, while a small fraction will have pronounced responses, and (b) likely to derive the greatest benefit from combination therapy.