Personalized CFTR Modulator Therapy for <i>G85E</i> and <i>N1303K</i> Homozygous Patients with Cystic Fibrosis
CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare <i>CFTR</i> mutations responsive in Fischer rat thyroid cells, including <i>G85E...
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/15/12365 |
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| author | Simon Y. Graeber Anita Balázs Niklas Ziegahn Tihomir Rubil Constanze Vitzthum Linus Piehler Marika Drescher Kathrin Seidel Alexander Rohrbach Jobst Röhmel Stephanie Thee Julia Duerr Marcus A. Mall Mirjam Stahl |
| author_facet | Simon Y. Graeber Anita Balázs Niklas Ziegahn Tihomir Rubil Constanze Vitzthum Linus Piehler Marika Drescher Kathrin Seidel Alexander Rohrbach Jobst Röhmel Stephanie Thee Julia Duerr Marcus A. Mall Mirjam Stahl |
| author_sort | Simon Y. Graeber |
| collection | DOAJ |
| description | CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare <i>CFTR</i> mutations responsive in Fischer rat thyroid cells, including <i>G85E</i>, but not <i>N1303K</i>. However, knowledge on the effect of ETI on G85E or N1303K CFTR function remains limited. In vitro effects of ETI were measured in primary human nasal epithelial cultures (pHNECs) of a <i>G85E</i> homozygous patient and an <i>N1303K</i> homozygous patient. Effects of ETI therapy in vivo in these patients were assessed using clinical outcomes, including multiple breath washout and lung MRI, and the CFTR biomarkers sweat chloride concentration (SCC), nasal potential difference (NPD) and intestinal current measurement (ICM), before and after initiation of ETI. ETI increased CFTR-mediated chloride transport in <i>G85E</i>/<i>G85E</i> and <i>N1303K</i>/<i>N1303K</i> pHNECs. In the <i>G85E</i>/<i>G85E</i> and the <i>N1303K</i>/<i>N1303K</i> patient, we observed an improvement in lung function, SCC, and CFTR function in the respiratory and rectal epithelium after initiation of ETI. The approach of combining preclinical in vitro testing with subsequent in vivo verification can facilitate access to CFTR modulator therapy and enhance precision medicine for patients carrying rare <i>CFTR</i> mutations. |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T00:25:50Z |
| publishDate | 2023-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d890a23b213e44b49515a4f60810d7b52023-11-18T23:04:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-08-0124151236510.3390/ijms241512365Personalized CFTR Modulator Therapy for <i>G85E</i> and <i>N1303K</i> Homozygous Patients with Cystic FibrosisSimon Y. Graeber0Anita Balázs1Niklas Ziegahn2Tihomir Rubil3Constanze Vitzthum4Linus Piehler5Marika Drescher6Kathrin Seidel7Alexander Rohrbach8Jobst Röhmel9Stephanie Thee10Julia Duerr11Marcus A. Mall12Mirjam Stahl13Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyDepartment of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, GermanyCFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare <i>CFTR</i> mutations responsive in Fischer rat thyroid cells, including <i>G85E</i>, but not <i>N1303K</i>. However, knowledge on the effect of ETI on G85E or N1303K CFTR function remains limited. In vitro effects of ETI were measured in primary human nasal epithelial cultures (pHNECs) of a <i>G85E</i> homozygous patient and an <i>N1303K</i> homozygous patient. Effects of ETI therapy in vivo in these patients were assessed using clinical outcomes, including multiple breath washout and lung MRI, and the CFTR biomarkers sweat chloride concentration (SCC), nasal potential difference (NPD) and intestinal current measurement (ICM), before and after initiation of ETI. ETI increased CFTR-mediated chloride transport in <i>G85E</i>/<i>G85E</i> and <i>N1303K</i>/<i>N1303K</i> pHNECs. In the <i>G85E</i>/<i>G85E</i> and the <i>N1303K</i>/<i>N1303K</i> patient, we observed an improvement in lung function, SCC, and CFTR function in the respiratory and rectal epithelium after initiation of ETI. The approach of combining preclinical in vitro testing with subsequent in vivo verification can facilitate access to CFTR modulator therapy and enhance precision medicine for patients carrying rare <i>CFTR</i> mutations.https://www.mdpi.com/1422-0067/24/15/12365cystic fibrosisCFTRCFTR modulatorG85EN1303Khuman nasal epithelial cells |
| spellingShingle | Simon Y. Graeber Anita Balázs Niklas Ziegahn Tihomir Rubil Constanze Vitzthum Linus Piehler Marika Drescher Kathrin Seidel Alexander Rohrbach Jobst Röhmel Stephanie Thee Julia Duerr Marcus A. Mall Mirjam Stahl Personalized CFTR Modulator Therapy for <i>G85E</i> and <i>N1303K</i> Homozygous Patients with Cystic Fibrosis International Journal of Molecular Sciences cystic fibrosis CFTR CFTR modulator G85E N1303K human nasal epithelial cells |
| title | Personalized CFTR Modulator Therapy for <i>G85E</i> and <i>N1303K</i> Homozygous Patients with Cystic Fibrosis |
| title_full | Personalized CFTR Modulator Therapy for <i>G85E</i> and <i>N1303K</i> Homozygous Patients with Cystic Fibrosis |
| title_fullStr | Personalized CFTR Modulator Therapy for <i>G85E</i> and <i>N1303K</i> Homozygous Patients with Cystic Fibrosis |
| title_full_unstemmed | Personalized CFTR Modulator Therapy for <i>G85E</i> and <i>N1303K</i> Homozygous Patients with Cystic Fibrosis |
| title_short | Personalized CFTR Modulator Therapy for <i>G85E</i> and <i>N1303K</i> Homozygous Patients with Cystic Fibrosis |
| title_sort | personalized cftr modulator therapy for i g85e i and i n1303k i homozygous patients with cystic fibrosis |
| topic | cystic fibrosis CFTR CFTR modulator G85E N1303K human nasal epithelial cells |
| url | https://www.mdpi.com/1422-0067/24/15/12365 |
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