Prime Editing Modification with FEN1 Improves F508del Variant Editing in the CFTR Gene in Airway Basal Cells

Prime editing is a promising approach for correcting pathogenic variants, but its efficiency remains variable across genomic contexts. Here, we systematically evaluated 12 modifications of the PEmax system for correcting the <i>CFTR</i> F508del pathogenic variant that caused cystic fibrosis in patient-derived airway basal cells. We chose EXO1 and FEN1 nucleases to improve the original system. While all tested variants showed comparatively low efficiency in this AT-rich genomic region, 4-FEN modification demonstrated significantly improved editing rates (up to 2.13 fold) compared to standard PEmax. Our results highlight two key findings: first, the persistent challenge of AT-rich target sequence correction even with optimized editors, and second, the performance of 4-FEN suggests its potential value for other genomic targets.

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Publication Details

Journal
International Journal of Molecular Sciences
Published
2025-08-18
DOI
https://doi.org/10.3390/ijms26167943
Primary Topic
CRISPR and Genetic Engineering
Type
article
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Prime Editing Modification with FEN1 Improves F508del Variant Editing in the CFTR Gene in Airway Basal Cells

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International Journal of Molecular Sciences
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article

Prime Editing Modification with FEN1 Improves F508del Variant Editing in the CFTR Gene in Airway Basal Cells

Olga Volodina, Andreyan Nikolaevich Osipov, Anna Demchenko, M. A. Ignatov, Valeriia Kovalskaia, E. V. Artemova, Ekaterina V. Kondrateva, Svetlana Smirnikhina, Arina A. Anuchina, А. В. Лавров, О. П. Рыжкова, Vyacheslav Tabakov, N. Yu. Vorobyeva
article en

Abstract

Prime editing is a promising approach for correcting pathogenic variants, but its efficiency remains variable across genomic contexts. Here, we systematically evaluated 12 modifications of the PEmax system for correcting the <i>CFTR</i> F508del pathogenic variant that caused cystic fibrosis in patient-derived airway basal cells. We chose EXO1 and FEN1 nucleases to improve the original system. While all tested variants showed comparatively low efficiency in this AT-rich genomic region, 4-FEN modification demonstrated significantly improved editing rates (up to 2.13 fold) compared to standard PEmax. Our results highlight two key findings: first, the persistent challenge of AT-rich target sequence correction even with optimized editors, and second, the performance of 4-FEN suggests its potential value for other genomic targets.

International Journal of Molecular SciencesVol. 26(16)
Moscow Institute of Physics and Technology (RU), Institute for Systems Analysis (RU), Research Centre for Medical Genetics (RU), State Scientific Center of the Russian Federation - Federal Medical Biophysical Center named after A.I. Burnazyan (RU)
Openalex Percentile: Top 81%
CRISPR and Genetic Engineering
DOIOpen Access PDFOpenAlex
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