Academic Journal
Clinical, functional and therapeutic evaluation of CFTR variant I507del.
| Τίτλος: | Clinical, functional and therapeutic evaluation of CFTR variant I507del. |
|---|---|
| Συγγραφείς: | Sharma N; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: nsharma5@jh.edu., Starego K; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Li H; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK., Kleist AB; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Cox G; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Havens M; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Neneh JS; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Parr A; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Merlo NA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Ren CL; Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA USA., Vanscoy L; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Raraigh KS; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Merlo C; Department of Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore MD, USA., Sheppard DN; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK., Cutting GR; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. |
| Πηγή: | Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society [J Cyst Fibros] 2026 Jul; Vol. 25 (4), pp. 745-752. Date of Electronic Publication: 2026 Feb 25. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101128966 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-5010 (Electronic) Linking ISSN: 15691993 NLM ISO Abbreviation: J Cyst Fibros Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Amsterdam ; New York : Elsevier, c2002- |
| Ιατρικοί όροι (MeSH): | Cystic Fibrosis Transmembrane Conductance Regulator*/genetics , Cystic Fibrosis Transmembrane Conductance Regulator*/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator*/drug effects , Cystic Fibrosis*/genetics , Cystic Fibrosis*/drug therapy , Cystic Fibrosis*/metabolism , Aminophenols*/therapeutic use , Aminophenols*/pharmacology , Benzodioxoles*/therapeutic use , Benzodioxoles*/pharmacology , Quinolones*/therapeutic use , Quinolones*/pharmacology , Indoles*/therapeutic use , Indoles*/pharmacology, Oximes/therapeutic use ; Oximes/pharmacology ; Chloride Channel Agonists/therapeutic use ; Chloride Channel Agonists/pharmacology ; Pyrazoles/therapeutic use ; Pyrazoles/pharmacology ; Pyridines/therapeutic use ; Pyridines/pharmacology ; Nasal Mucosa/metabolism ; Humans ; Drug Combinations ; Cells, Cultured ; Pyrrolidines ; Quinolines |
| Περίληψη: | 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. (Copyright © 2026 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors have nothing to disclose. |
| Grant Information: | R01 DK044003 United States DK NIDDK NIH HHS |
| Contributed Indexing: | Keywords: CFTR function; Elexacaftor; F508del; I507del; Ivacaftor; Tezacaftor; Vanzacaftor; mRNA abundance |
| Substance Nomenclature: | 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) 0 (Aminophenols) 0 (Benzodioxoles) 0 (Quinolones) 0 (Indoles) 0 (Drug Combinations) 0 (Oximes) 0 (Chloride Channel Agonists) 0 (CFTR protein, human) RRN67GMB0V (elexacaftor) 0 (Pyrazoles) 0 (Pyridines) 0 (elexacaftor, ivacaftor, tezacaftor drug combination) 8RW88Y506K (tezacaftor) 0 (tezacaftor, ivacaftor drug combination) 0 (Pyrrolidines) 0 (Quinolines) |
| Entry Date(s): | Date Created: 20260225 Date Completed: 20260730 Latest Revision: 20260730 |
| Update Code: | 20260731 |
| PubMed Central ID: | PMC13122485 |
| DOI: | 10.1016/j.jcf.2026.02.013 |
| PMID: | 41741303 |
| Βάση Δεδομένων: | MEDLINE |
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