CFTR modulators response of S737F and T465N CFTR variants on patient-derived rectal organoids.

Autor: Kleinfelder K; Department of Medicine, Division of General Pathology, Cystic Fibrosis Laboratory 'D. Lissandrini', University of Verona, 37134, Verona, Italy., Melotti P; Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria Integrata Verona, 37126, Verona, Italy., Hristodor AM; Cystic Fibrosis Centre, Azienda Ospedaliera Universitaria Integrata Verona, 37126, Verona, Italy., Fevola C; Department of Pediatric Medicine, Meyer Children's Hospital IRCCS, Cystic Fibrosis Regional Reference Center, Florence, Italy., Taccetti G; Department of Pediatric Medicine, Meyer Children's Hospital IRCCS, Cystic Fibrosis Regional Reference Center, Florence, Italy., Terlizzi V; Department of Pediatric Medicine, Meyer Children's Hospital IRCCS, Cystic Fibrosis Regional Reference Center, Florence, Italy. vito.terlizzi@meyer.it., Sorio C; Department of Medicine, Division of General Pathology, Cystic Fibrosis Laboratory 'D. Lissandrini', University of Verona, 37134, Verona, Italy. claudio.sorio@univr.it.
Jazyk: angličtina
Zdroj: Orphanet journal of rare diseases [Orphanet J Rare Dis] 2024 Sep 13; Vol. 19 (1), pp. 343. Date of Electronic Publication: 2024 Sep 13.
DOI: 10.1186/s13023-024-03334-3
Abstrakt: Background: Predictions based on patient-derived materials of CFTR modulators efficacy have been performed lately in patient-derived cells, extending FDA-approved drugs for CF patients harboring rare variants. Here we developed intestinal organoids from subjects carrying S737F- and T465N-CFTR in trans with null alleles to evaluate their functional impact on CFTR protein function and their restoration upon CFTR modulator treatment. The characterization of S737F-CFTR was performed in two subjects recently assessed in nasal epithelial cells but not in colonoids.
Results: Our functional analysis (Ussing chamber) confirmed that S737F-CFTR is a mild variant with residual function as investigated in colonoids of patients with S737F/Dele22-24 and S737F/W1282X genotypes. An increase of current upon Elexacaftor/Tezacaftor/Ivacaftor (ETI) treatment was recorded for the former genotype. T465N is a poorly characterized missense variant that strongly impacts CFTR function, as almost no CFTR-mediated anion secretion was registered for T465N/Q39X colonoids. ETI treatment substantially improved CFTR-mediated anion secretion and increased the rescue of mature CFTR expression compared to either untreated colonoids or to dual CFTR modulator therapies.
Conclusions: Our study confirms the presence of a residual function of the S737F variant and its limited response to CFTR modulators while predicting for the first time the potential clinical benefit of Trikafta® for patients carrying the rare T465N variant.
(© 2024. The Author(s).)
Databáze: MEDLINE
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