Wine Jeffrey J
Cystic Fibrosis Research Laboratory, Department of Psychology, Human Biology and (by courtesy) Pediatrics, Stanford University, Room 210, Bldg. 420, Jane Stanford Way, Stanford, CA 94305-2130, USA.
J Cyst Fibros. 2024 Nov;23(6):1180-1184. doi: 10.1016/j.jcf.2024.09.004. Epub 2024 Oct 15.
It is difficult to determine CFTR activity following highly effective CFTR modulator therapies (HEMT). The sweat gland provides two biomarkers of CFTR activity: a linear readout via the β-sweat rate and a logarithmic readout via sweat chloride concentration (SCC). In prior work, different logarithmic functions were generated to calibrate SCC with the percent of healthy control CFTR activity (HCCFTR). Two functions, A and B, were fit to SCC means from healthy controls set = 100 % and CF carriers measured as 50 % HCCFTR. A and B differ in the % HCCFTR activity assigned to SCC for minimal function mutations = 0.01 % for A and 1 % for B.
Here, the functions are evaluated based on retrospective analysis of three multi-center studies of CF subjects with one or two F508del mutations treated with Elexacaftor/Tezacaftor/Ivacaftor (ETI). Predictions of the percent HCCFTR activity for one vs two mutations were compared for the two functions. The expectation is that after ETI treatment, subjects with two responsive mutations will have 2-fold higher HCCFTR activity than subjects with only one. The hypothesis is that the SCCHCCFTR function that most closely fits that expectation provides the more accurate prediction of CFTR activity.
In two separate comparisons, function B most accurately predicted a 2-fold (1.9, 2.3-fold) higher level of HCCFTR activity in subjects on ETI with two vs. one responsive mutation. Function A predicted a 4, 5.5-fold higher level.
Function B predicts that 60 mmol/L SCC, the cutoff for a CF diagnosis, is associated with 10 % HCCFTR activity. Comparing HEMT effects on subjects with one or two mutations provides an additional tool for calibrating SCC to CFTR activity.
在高效的囊性纤维化跨膜传导调节因子（CFTR）调节剂疗法（HEMT）之后，很难确定CFTR的活性。汗腺提供了CFTR活性的两种生物标志物：通过β汗液分泌率的线性读数和通过汗液氯化物浓度（SCC）的对数读数。在先前的研究中，生成了不同的对数函数，以将SCC与健康对照CFTR活性（HCCFTR）的百分比进行校准。两个函数，A和B，拟合了健康对照设定为100%的SCC均值以及测量为50%HCCFTR的CF携带者的SCC均值。A和B在分配给最小功能突变的SCC的HCCFTR活性百分比上有所不同，A为0.01%，B为1%。
在此，基于对三项多中心研究的回顾性分析来评估这些函数，这些研究涉及患有一个或两个F508del突变且接受依列卡福/替扎卡福/依伐卡福（ETI）治疗的CF患者。比较了这两个函数对一个与两个突变的HCCFTR活性百分比的预测。预期是在ETI治疗后，具有两个反应性突变的患者的HCCFTR活性将比仅具有一个突变的患者高2倍。假设是最符合该预期的SCCHCCFTR函数能提供对CFTR活性更准确的预测。
在两次单独的比较中，函数B最准确地预测了接受ETI治疗且有两个与一个反应性突变的患者中，HCCFTR活性水平高2倍（1.9倍、2.3倍）。函数A预测的水平高4倍、5.5倍。
函数B预测，CF诊断的临界值60 mmol/L SCC与10%的HCCFTR活性相关。比较HEMT对具有一个或两个突变的患者的影响，为将SCC校准为CFTR活性提供了一个额外的工具。
