Data from: The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: human in vivo measurements

We optically measured effects of orally available ivacaftor (Kalydeco®) on sweat rates of identified glands in 3 R117H subjects, each having a unique set of additional mutations, and compared them with 5 healthy control subjects tested contemporaneously. We injected β-adrenergic agonists intradermally to stimulate CFTR-dependent ‘C-sweat’ and methacholine to stimulate ‘M-sweat’, which persists in CF subjects. We focused on an R117H-7T/F508del subject who produced quantifiable C-sweat off ivacaftor and was available for 1 blinded, 3 off ivacaftor, and 3 on ivacaftor tests, allowing us to estimate in vivo fold-increase in sweat rates produced by ivacaftor’s effect on the open probability (PO) of R117H-CFTR. Measured sweat rates must be corrected for sweat losses. With estimated sweat losses of 0.023 to 0.08 nl·gland-1·min-1, ivacaftor increased the average C-sweat rates 3-7 fold, and estimated function as % of WT were 4.1-12% off ivacaftor and 21.9-32% on ivacaftor (larger values reflect increased loss estimates). Based on single tests, an R117H-7T/ R117H-7T subject showed 6-9% WT function off ivacaftor and 28-43% on ivacaftor. Repeat testing of an R117H-5T/F508del subject detected only trace responding to ivacaftor. We conclude that in vivo, R117H PO is strongly increased by ivacaftor, but channel number, mainly determined by variable deletion of exon 10, has a marked influence on outcomes.

我们通过光学检测方法，评估了口服依伐卡托（ivacaftor，商品名Kalydeco®）对3名携带R117H突变受试者的已识别汗腺出汗速率的影响——每名受试者均携带有独特的额外突变组合，并将结果与同期检测的5名健康对照受试者进行对比。我们通过皮内注射β-肾上腺素能激动剂，以刺激依赖囊性纤维化跨膜传导调节因子（Cystic Fibrosis Transmembrane Conductance Regulator，CFTR）的‘C型出汗’；同时注射乙酰甲胆碱，以刺激持续存在于囊性纤维化（cystic fibrosis，CF）受试者体内的‘M型出汗’。我们重点关注了一名携带R117H-7T/F508del突变的受试者：该受试者在未服用依伐卡托时即可产生可量化的C型出汗，且可完成1次盲法检测、3次未服用依伐卡托时的检测以及3次服用依伐卡托时的检测。这使得我们能够估算依伐卡托通过影响R117H-CFTR的开放概率（open probability，Pₒ）所带来的体内出汗速率增幅倍数。实测出汗速率需针对汗液流失量进行校正。当估算的汗液流失量为0.023~0.08 nl·腺体⁻¹·分钟⁻¹时，依伐卡托可使平均C型出汗速率提升3~7倍；未服用依伐卡托时，受试者的CFTR功能估算值（以野生型（wild type，WT）的功能为100%计）为4.1%~12%，服用依伐卡托后则升至21.9%~32%（数值越高代表汗液流失量估算值越高）。基于单次检测结果，一名携带R117H-7T/R117H-7T突变的受试者在未服用依伐卡托时的CFTR功能为野生型的6%~9%，服用依伐卡托后则升至28%~43%。对一名携带R117H-5T/F508del突变的受试者进行重复检测后发现，其对依伐卡托的响应仅为微量。我们的研究结论如下：在体内环境中，依伐卡托可显著提升R117H突变CFTR的开放概率，但主要由第10外显子可变缺失所决定的通道数量，会对治疗结局产生显著影响。