Personalized CFTR Modulator Therapy for <i>G85E</i> and <i>N1303K</i> Homozygous Patients with Cystic Fibrosis

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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Bibliographic Details
Main Authors: 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
Format: Article
Language:English
Published: MDPI AG 2023-08-01
Series:International Journal of Molecular Sciences
Subjects:
cystic fibrosis
CFTR
CFTR modulator
G85E
N1303K
human nasal epithelial cells
Online Access:https://www.mdpi.com/1422-0067/24/15/12365
Description
Summary: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.
ISSN:1661-6596
1422-0067

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