CFTRバリアントI507delの臨床的、機能的、および治療的評価

Small-molecule CFTR modulators target variants that allow CFTR protein production, but clinically relevant response depends on modulator effectiveness. One such variant is I507del (p.Ile507del, c.1519_1521delATC) and its location (adjacent to F508del) may encourage empirical treatment with modulators. Consequently, we have performed studies to inform management of individuals with CF bearing I507del. CFTR2 lists 704 individuals with I507del and a severe variant, with clinical features like F508del homozygotes (pancreatic insufficiency 96%, mean ppFEV1 70%, mean sweat chloride 102 mM). In primary human nasal epithelial (HNE) cultures from two donors carrying I507del and a null variant (2184delA or 621+1G>T), baseline CFTR activity was <1% of wild-type (WT) (0.11-0.16 µA/cm²) and elexacaftor-tezacaftor-ivacaftor (ETI) failed to increase function. Immortalized Flp-In-cystic fibrosis bronchial epithelial (CFBE) cells expressing I507del likewise showed negligible ETI response, and Western blots revealed the absence of mature CFTR protein. Single-channel patch-clamp studies detected rare CFTR openings in 14% of membrane patches after prolonged low-temperature plus ETI treatment, revealing conductance in the context of a profound folding defect. Vanzacaftor/tezacaftor/ivacaftor (VTI) reproducibly restored ∼6.4% WT (1.14 ± 0.4 µA/cm²) activity in donor-derived HNEs and produced mature CFTR protein in Flp-In-CFBE models. In Flp-In-CFBE clones, the magnitude of the VTI-mediated recovery correlated with RNA abundance (r² = 0.95). The robust RNA-function relationship highlights RNA amplification strategies as potential adjuncts to increase rescue. These findings identify I507del as an ETI-refractory allele with minimal responsiveness to VTI suggesting careful consideration before embarking upon modulator treatment of individuals with CF carrying this variant.