2. Academic Validation
  3. Evaluation of the response to elexacaftor-tezacaftor-ivacaftor of the rare CFTR variants L383S, I507del, L1065P and R1066H in intestinal organoid-derived epithelial monolayers

Evaluation of the response to elexacaftor-tezacaftor-ivacaftor of the rare CFTR variants L383S, I507del, L1065P and R1066H in intestinal organoid-derived epithelial monolayers

  • J Cyst Fibros. 2025 Feb 19:S1569-1993(25)00059-1. doi: 10.1016/j.jcf.2025.02.008.
Jessica Conti 1,  Dora Angyal 2,  Karina Kleinfelder 1,  Roberta Valeria Latorre 1,  Martina Calicchia 1,  Alessia Farinazzo 1,  Luca Rodella 3,  Francesco Tomba 3,  Arianna Massella 3,  Luca Frulloni 4,  Giovanni Taccetti 5,  Vito Terlizzi 5,  Anny Leung 2,  Tessa A Groeneweg 2,  Marcel J C Bijvelds 2,  Paola Melotti 6,  Claudio Sorio 7
Affiliations

Affiliations

  • 1 Department of Medicine, University of Verona, Division of General Pathology, Cystic Fibrosis Laboratory "D. Lissandrini", Verona, Italy.
  • 2 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
  • 3 Endoscopy Surgery Unit, Azienda Ospedaliera Universitaria Integrata Verona, 37126 Verona, Italy.
  • 4 Gastroenterology Unit, Department of Medicine, Borgo Roma Hospital, Piazzale L.A. Scuro 10, 37134 Verona, Italy.
  • 5 Meyer Children's Hospital IRCCS, Cystic Fibrosis Regional Reference Center, Department of Paediatric Medicine, Florence, Italy.
  • 6 Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.
  • 7 Department of Medicine, University of Verona, Division of General Pathology, Cystic Fibrosis Laboratory "D. Lissandrini", Verona, Italy. Electronic address: claudio.sorio@univr.it.
PMID: 39979195 DOI: 10.1016/j.jcf.2025.02.008
Abstract

Introduction: Cystic fibrosis (CF) is caused by mutation of the CFTR gene, encoding an epithelial anion channel. Here we evaluated the effect of the modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) on the function of four rare, poorly characterized CFTR variants: L383S, I507del, L1065P and R1066H.

Methods: Intestinal organoids were obtained from subjects carrying the CFTR variants L383S, I507del, L1065P or R1066H in trans of a minimal function allele (class I mutation). Organoids and epithelial monolayers were used to assess the effect of ETI on CFTR protein abundance and CFTR-mediated chloride, bicarbonate, and fluid transport.

Results: In L383S-CFTR expressing cells, normal levels of fully glycosylated CFTR protein (C-band) were detected. In contrast, in I507del, L1065P or R1066H organoids, only partially glycosylated CFTR (B-band) was detected. Chloride/bicarbonate transport was severely impaired in epithelial monolayers prepared from these latter three variants, while anion transport of the L383S variant was affected to a moderate extent. ETI, but not ivacaftor alone, significantly enhanced CFTR-mediated chloride and bicarbonate transport in L1065P and R1066H monolayers, and stimulated fluid transport. A corresponding increase in the abundance of C-band protein was observed in both variants. ETI also modestly improved L383S-CFTR function, with a marginal effect on I507del-CFTR.

Conclusions: The I507del, L1065P and R1066H variants display severely impaired function. ETI treatment markedly enhanced L1065P- and R1066HCFTR function, whereas its effect on L383S- CFTR was less pronounced. Consequently, ETI may ameliorate disease symptoms in individuals carrying the L1065P or R1066H variant. More tentative, it may also benefit those carrying the L383S variant.

Keywords

Cftr variants, bicarbonate secretion; Cystic fibrosis; Personalized medicine; Rectal organoids; Theratyping; Ussing chamber.

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