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Background <p>Despite the approval of CFTR modulator (CFTRm) drugs for specific variants, many people with cystic fibrosis with non-eligible genotypes may still benefit from these medications. Indeed, recent studies show that some rare CFTR variants can be rescued by approved CFTRm drugs.</p> Objective <p>we assessed the efficacy of CFTRm drugs on eight rare CFTR variants: p.Pro5Leu, p.Pro205Ser, p.Leu206Trp, p.Arg347Pro, p.Ile507del, p.Ser945Leu, p.Met1137Arg, and p.Asp1152His.</p> Methods <p>Patient-derived intestinal organoids with these variants in heterozygosity with other cystic fibrosis-causing ones were analyzed by the forskolin-induced swelling assay. Clinical data from individuals undergoing CFTRm therapy were collected both before and after treatment to evaluate clinical benefit. Furthermore, we characterized the molecular defect of those eight variants individually in cystic fibrosis bronchial epithelial cells.</p> Results <p>CFTR function in intestinal organoids with genotypes p.Asp1152His/p.Phe508del, p.Asp1152His/p.Asn1303Lys, p.Pro5Leu/p.Phe508del, p.Leu206Trp/p.Phe508del, p.Ser945Leu/p.Phe508del, p.Pro205Ser/p.Tyr1092Ter, and p.Met1137Arg/c.2657+5G&gt;A was rescued by currently available CFTRm drugs, this was not observed for organoids with genotypes p.Arg347Pro/p.Phe508del (elexacaftor/tezacaftor/ivacaftor was not tested) and p.Ile507del/p.Gln890Ter. People with cystic fibrosis who, based on our data, started CFTRm therapy showed a clinical improvement, including an increase in lung function, and a reduction in sweat chloride levels. A positive correlation was observed between forskolin-induced swelling values and change in forced expiratory volume in 1 second. This study provides evidence that the forskolin-induced swelling assay using patient-derived intestinal organoids can effectively predict the clinical outcome of CFTRm treatment. In CFBE cells, all eight variants were found to have a processing defect and variants p.Pro5Leu, p.Pro205Ser, p.Leu206Trp, p.Arg347Pro, p.Ser945Leu, and p.Met1137Arg were functionally rescued by the current available CFTRm drug. The CFTRm drug did not elicit the appearance of mature p.Ile507del-CFTR and increased, albeit not significantly, the processing efficiency of p.Asp1152His-CFTR.</p> Conclusions <p>This work highlights the importance of using patient-derived intestinal organoids as a theranostic tool to predict the clinical benefit and thus increase the number of people with cystic fibrosis with access to the currently approved CFTRm therapies. While theratyping in cell lines is a valuable approach, additional testing in cystic fibrosis-derived organoids provides more reliable predictions for the individuals carrying rare CFTR variants.</p>

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Personalized Medicine in Cystic Fibrosis: Characterization of Eight Rare CFTR Variants in Intestinal Organoids and Cellular Models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月13日

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  • Violeta Railean,
  • Cláudia S. Rodrigues,
  • Ines Pankonien,
  • Sofia S. Ramalho,
  • Iris A. L. Silva,
  • Tereza Doušová,
  • Susana Castanhinha,
  • Pilar Azevedo,
  • Juliana Roda,
  • Carlos M. Farinha,
  • Margarida D. Amaral

摘要

Background

Despite the approval of CFTR modulator (CFTRm) drugs for specific variants, many people with cystic fibrosis with non-eligible genotypes may still benefit from these medications. Indeed, recent studies show that some rare CFTR variants can be rescued by approved CFTRm drugs.

Objective

we assessed the efficacy of CFTRm drugs on eight rare CFTR variants: p.Pro5Leu, p.Pro205Ser, p.Leu206Trp, p.Arg347Pro, p.Ile507del, p.Ser945Leu, p.Met1137Arg, and p.Asp1152His.

Methods

Patient-derived intestinal organoids with these variants in heterozygosity with other cystic fibrosis-causing ones were analyzed by the forskolin-induced swelling assay. Clinical data from individuals undergoing CFTRm therapy were collected both before and after treatment to evaluate clinical benefit. Furthermore, we characterized the molecular defect of those eight variants individually in cystic fibrosis bronchial epithelial cells.

Results

CFTR function in intestinal organoids with genotypes p.Asp1152His/p.Phe508del, p.Asp1152His/p.Asn1303Lys, p.Pro5Leu/p.Phe508del, p.Leu206Trp/p.Phe508del, p.Ser945Leu/p.Phe508del, p.Pro205Ser/p.Tyr1092Ter, and p.Met1137Arg/c.2657+5G>A was rescued by currently available CFTRm drugs, this was not observed for organoids with genotypes p.Arg347Pro/p.Phe508del (elexacaftor/tezacaftor/ivacaftor was not tested) and p.Ile507del/p.Gln890Ter. People with cystic fibrosis who, based on our data, started CFTRm therapy showed a clinical improvement, including an increase in lung function, and a reduction in sweat chloride levels. A positive correlation was observed between forskolin-induced swelling values and change in forced expiratory volume in 1 second. This study provides evidence that the forskolin-induced swelling assay using patient-derived intestinal organoids can effectively predict the clinical outcome of CFTRm treatment. In CFBE cells, all eight variants were found to have a processing defect and variants p.Pro5Leu, p.Pro205Ser, p.Leu206Trp, p.Arg347Pro, p.Ser945Leu, and p.Met1137Arg were functionally rescued by the current available CFTRm drug. The CFTRm drug did not elicit the appearance of mature p.Ile507del-CFTR and increased, albeit not significantly, the processing efficiency of p.Asp1152His-CFTR.

Conclusions

This work highlights the importance of using patient-derived intestinal organoids as a theranostic tool to predict the clinical benefit and thus increase the number of people with cystic fibrosis with access to the currently approved CFTRm therapies. While theratyping in cell lines is a valuable approach, additional testing in cystic fibrosis-derived organoids provides more reliable predictions for the individuals carrying rare CFTR variants.