Targeted knock-in of NCF1 cDNA into the NCF2 locus leads to myeloid phenotypic correction of p47 -deficient chronic granulomatous disease

Siow, Kah Mun; Güngör, Merve; Wrona, Dominik; Raimondi, Federica; Pastukhov, Oleksandr; Tsapogas, Panagiotis; Menzi, Timon; Schmitz, Michael; Kulcsár, Péter István; Schwank, Gerald; Schulz, Ansgar; Jinek, Martin; Modlich, Ute; Siler, Ulrich; Reichenbach, Janine

doi:10.1016/j.omtn.2024.102229

Molecular Therapy - Nucleic Acids

2024

DOI: 10.1016/j.omtn.2024.102229

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Targeted knock-in of NCF1 cDNA into the NCF2 locus leads to myeloid phenotypic correction of p47 -deficient chronic granulomatous disease

Kah Mun Siow,

Merve Güngör,

Dominik Wrona

et al.

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2024

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Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements

Raimondi,

Siow,

Wrona

et al. 2024

Commun Biol

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CRISPR-based genome editing of pseudogene-associated disorders, such as p47 phox -deficient chronic granulomatous disease (p47 CGD), is challenged by chromosomal rearrangements due to presence of multiple targets. We report that interactions between highly homologous sequences that are localized on the same chromosome contribute substantially to post-editing chromosomal rearrangements. We successfully employed editing approaches at the NCF1 gene and its pseudogenes, NCF1B and NCF1C , in a human cell line model of p47 CGD and in patient-derived human hematopoietic stem and progenitor cells. Upon genetic engineering, a droplet digital PCR-based method identified cells with altered copy numbers, spanning megabases from the edited loci. We attributed the high aberration frequency to the interaction between repetitive sequences and their predisposition to recombination events. Our findings emphasize the need for careful evaluation of the target-specific genomic context, such as the presence of homologous regions, whose instability can constitute a risk factor for chromosomal rearrangements upon genome editing.

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Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements

Raimondi,

Siow,

Wrona

et al. 2024

Commun Biol

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Targeted knock-in of NCF1 cDNA into the NCF2 locus leads to myeloid phenotypic correction of p47 -deficient chronic granulomatous disease

Cited by 1 publication

References 82 publications

Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements

Gene editing of NCF1 loci is associated with homologous recombination and chromosomal rearrangements

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