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Background <p>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 <i>in trans</i> 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).</p> Results <p>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<sub>SC</sub>) 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.</p> Conclusions <p>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.</p>

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Characterization of two ultra-rare CFTR variants, P.Leu999del and P.Glu1104Lys, with unknown theratyping profiles

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Tereza Dousova,
  • Lucie Borek-Dohalska,
  • Stepanka Novotna,
  • Veronika Skalicka,
  • Malgorzata Libik,
  • Milan Macek Jr,
  • Pavel Drevinek

摘要

Background

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).

Results

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 ISC) 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.

Conclusions

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.