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

Bat El Bar Aluma; Joel Reiter; Ori Efrati; Yael Bezalel; Shlomit Keler; Moshe Ashkenazi; Adi Dagan; Yael Buchnik; Ido Sadras; Malena Cohen-Cymberknoh

doi:10.1016/j.jcf.2024.02.008

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

J Cyst Fibros. 2024 Mar 4:S1569-1993(24)00019-5. doi: 10.1016/j.jcf.2024.02.008. Online ahead of print.

Authors

Affiliations

¹ Pediatric Pulmonary Unit and Cystic fibrosis Center, Lily and Edmond Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: batel.baraluma@sheba.health.gov.il.
² Pediatric Pulmonary Unit and Cystic fibrosis Center, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel.
³ Pediatric Pulmonary Unit and Cystic fibrosis Center, Lily and Edmond Safra Children's Hospital, Sheba Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

PMID: 38443268
DOI: 10.1016/j.jcf.2024.02.008

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: This study supports a clinical benefit for CFTRm therapy in pwCF carrying the I1234V mutation.

Keywords: CFTR modulators; Elexacaftor/Tezacaftor/Ivacaftor; I1234V CFTR mutation.