Clinical efficacy of CFTR modulator therapy in people with cystic fibrosis carrying the I1234V mutation

• Published in: Journal of cystic fibrosis Vol. 23; no. 4; pp. 685 - 689
• Main Authors: Aluma, Bat El Bar, Reiter, Joel, Efrati, Ori, Bezalel, Yael, Keler, Shlomit, Ashkenazi, Moshe, Dagan, Adi, Buchnik, Yael, Sadras, Ido, Cohen-Cymberknoh, Malena
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2024
• Subjects: Adult; Aminophenols - therapeutic use; Aminopyridines - therapeutic use; Benzodioxoles - therapeutic use; CFTR modulators; Chloride Channel Agonists - therapeutic use; Cystic Fibrosis - drug therapy; Cystic Fibrosis - genetics; Cystic Fibrosis - physiopathology; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Drug Combinations; Elexacaftor/Tezacaftor/Ivacaftor; Female; Forced Expiratory Volume; Humans; I1234V CFTR mutation; Indoles - therapeutic use; Male; Mutation, Missense; Quinolones - therapeutic use; Retrospective Studies; Sweat - chemistry; Treatment Outcome; Elexacaftor/Tezacaftor/Ivacaftor; CFTR modulators; I1234V CFTR mutation
• ISSN: 1569-1993; 1873-5010; 1873-5010
• DOI: 10.1016/j.jcf.2024.02.008

•The I1234V mutation is quite common among Arab-Muslim populations.•This mutation cause defective CFTR protein folding, similar to the F508 del mutation.•Currently, the I1234V mutation is not yet eligible for CFTR modulators.•CFTR modulator therapy resulted in significant clinical improvement. The cystic fibrosis transmembrane conductance regulator (CFTR) mutation I1234V (I1234V, p.Ile1234Val, c.3700A>G), is a missense-mutation that creates a cryptic splice site, with the formation of a protein lacking 6 amino acids, that is misfolded and misprocessed. The in vitro effects of CFTR modulator (CFTRm) therapies on human bronchial cell models and intestinal organoids carrying this mutation are conflicting. The aim of this study was therefore to explore the clinical efficacy of CFTRm in people with cystic fibrosis (pwCF) carrying this mutation. This was a retrospective descriptive study of the clinical records of homozygous and compound heterozygous (none F508del) pwCF, for the I1234V mutation, that received CFTRm. Parameters explored were body mass index (BMI), forced expiratory volume in one second percent predicted (FEV1%), lung clearance index (LCI) and quantitative sweat chloride measurements. Mean age was 38.6 ± 14 years (range 21–60). Two subjects were homozygous and five compound heterozygous, with minimal function mutations. Four were pancreatic insufficient and three pancreatic sufficient. The two homozygous subjects received Tezacaftor/Ivacaftor, the remaining Elexacaftor/Tezacaftor/Ivacaftor (ETI); treatment ranged from 6 to 12 months. Mean BMI score increased from 21.7 ± 1.3 to 23.6 ± 2.1 kg/m2 (p = 0.04); FEV1(%pred) increased by 20.14±10.2while mean change in FEV1 in the year prior to CFTRm initiation was -0.14±1.18 (p = 0.0001). Additionally, LCI 2.5% decreased from 18.7 to 14.5 (p = 0.07); sweat chloride decreased from 116±10 to 90±17 mEq/L (p = 0.017) and chronic pseudomonas airway infection was eradicated in one subject. This study supports a clinical benefit for CFTRm therapy in pwCF carrying the I1234V mutation.