伊瓦卡夫托
囊性纤维化
医学
突变
内科学
体外
囊性纤维化跨膜传导调节器
移码突变
胃肠病学
生物
遗传学
基因
作者
Ido Sadras,Eitan Kerem,Galit Livnat,Ifat Sarouk,Oded Breuer,Joel Reiter,Alex Gileles‐Hillel,Ori Inbar,Michael Cohen,Ayelet Gamliel,Noemie Stanleigh,Tarini Gunawardena,Claire Bartlett,Tanja Gonska,Theo J. Moraes,Paul D. W. Eckford,Christine E. Bear,Félix Ratjen,Batsheva Kerem,Michael Wilschanski,Michal Shteinberg,Malena Cohen‐Cymberknoh
标识
DOI:10.1016/j.jcf.2023.06.001
摘要
Background Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303K-CFTR activity. Based on the in vitro response, eight patients commenced treatment with ELX/TEZ/IVA. Methods Two homozygotes; and six compound heterozygotes N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from 5 study patients and an additional patient carrying N1303K that is not receiving treatment. Results Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 26.5% relative to baseline, mean BMI increased by 0.79 Kg/m2, and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity. Conclusions This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation have a significant clinical benefit by ELX/TEZ/IVA treatment.
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