两种极罕见的CFTR变体P.Leu999del和P.Glu1104Lys的特征，其治疗方案未知
Characterization of two ultra-rare CFTR variants, P.Leu999del and P.Glu1104Lys, with unknown theratyping profiles.
摘要(中文译文)
携带超罕见CFTR变异的个体因缺乏支持变异特异性反应性的功能和临床数据，仍未接受CFTR调节剂治疗。本研究旨在对两种超罕见CFTR变异p.Glu1104Lys（E1104K）和p.Leu999del（L999del）进行功能表征，这两种变异均与最小功能变异G542X呈反式排列，并评估其对三联组合方案elexacaftor/tezacaftor/ivacaftor（ELX/TEZ/IVA）和vanzacaftor/tezacaftor/ivacaftor（VAN/TEZ/IVA）的反应性。从两名囊性纤维化患者（G542X/E1104K和G542X/L999del）的直肠活检样本中培养患者来源的肠道类器官（PDIOs），并进行毛喉素诱导肿胀（FIS）实验。通过计算60分钟后的曲线下面积来量化CFTR功能。通过鼻刷获取人鼻上皮细胞（HNECs），在气液界面条件下扩增，并在Ussing室中进行评估。将对CFTRinh-172敏感的刺激电流（ΔCFTRinh-172 I）表示为健康对照组平均反应的百分比。两种PDIOs在未处理条件下均表现出可见肿胀，表明存在残余CFTR功能。经ELX/TEZ或VAN/TEZ预处理后，两者均出现明显的预肿胀，使定量分析仅限于定性评估。在HNECs中，E1104K和L999del的残余CFTR活性分别达到野生型水平的15%和13%。经调节剂处理后，E1104K的CFTR活性分别增至90%（ELX/TEZ）和97%（VAN/TEZ），L999del增至46%和56%。E1104K和L999del表现出可测量的残余CFTR功能以及对两种CFTRm三联组合方案的体外反应性。这些发现支持治疗诊断学方法以指导超罕见CFTR基因型个体的治疗，而临床使用仍取决于监管批准和个体化患者评估。
Abstract
Individuals carrying ultra-rare CFTR variants remain untreated with CFTR modulator therapies due to a lack of functional and clinical data supporting variant-specific responsiveness. This study aimed to functionally characterize two ultra-rare CFTR variants, p.Glu1104Lys (E1104K) and p.Leu999del (L999del), each found in trans with the minimal function variant G542X, and to evaluate their responsiveness to the triple-combination regimens elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and vanzacaftor/tezacaftor/ivacaftor (VAN/TEZ/IVA). Patient-derived intestinal organoids (PDIOs) of two people with cystic fibrosis (G542X/E1104K and G542X/L999del) were cultured from rectal biopsies and subjected to forskolin-induced swelling (FIS) assays. CFTR function was quantified by calculating the area under the curve after 60 minutes. Human nasal epithelial cells (HNECs) were obtained by nasal brushing, expanded under air-liquid interface conditions, and evaluated in Ussing chambers. CFTRinh-172-sensitive stimulated currents (ΔCFTRinh-172 I) were expressed as percentages of the mean response of healthy controls. Both PDIOs exhibited visible swelling under untreated conditions, indicating residual CFTR function. Following pretreatment with ELX/TEZ or VAN/TEZ, both showed marked pre-swelling limiting quantitative analysis to qualitative assessment. In HNECs, residual CFTR activity reached 15% and 13% of WT levels for E1104K and L999del, respectively. Upon modulator treatment, CFTR activity increased to 90% (ELX/TEZ) and 97% (VAN/TEZ) in E1104K, and to 46% and 56% in L999del. E1104K and L999del exhibit measurable residual CFTR function and in vitro responsiveness to two CFTRm triple-combination regimens. These findings support theranostic approaches to guide therapy in individuals with ultra-rare CFTR genotypes, while clinical use remains dependent on regulatory approval and individualized patient assessment.
如何引用
AMA
Tereza Dousova, Lucie Borek-Dohalska, Stepanka Novotna, Veronika Skalicka, Malgorzata Libik, Milan Macek, et al. Characterization of two ultra-rare CFTR variants, P.Leu999del and P.Glu1104Lys, with unknown theratyping profiles.. Orphanet journal of rare diseases. 2026; doi:10.1186/s13023-026-04415-1.
APA
Tereza Dousova, Lucie Borek-Dohalska, Stepanka Novotna, Veronika Skalicka, Malgorzata Libik, Milan Macek, et al (2026). Characterization of two ultra-rare CFTR variants, P.Leu999del and P.Glu1104Lys, with unknown theratyping profiles.. Orphanet journal of rare diseases. https://doi.org/10.1186/s13023-026-04415-1
GB/T 7714
Tereza Dousova, Lucie Borek-Dohalska, Stepanka Novotna, Veronika Skalicka, Malgorzata Libik, Milan Macek, et al. Characterization of two ultra-rare CFTR variants, P.Leu999del and P.Glu1104Lys, with unknown theratyping profiles.[J]. Orphanet journal of rare diseases, 2026 doi:10.1186/s13023-026-04415-1.
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