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Correction of a Factor VIII genomic inversion with designer-recombinases

Author

Listed:
  • Felix Lansing

    (Technical University Dresden)

  • Liliya Mukhametzyanova

    (Technical University Dresden)

  • Teresa Rojo-Romanos

    (Technical University Dresden)

  • Kentaro Iwasawa

    (Center for Stem Cell and Organoid Medicine (CuSTOM) Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Masaki Kimura

    (Center for Stem Cell and Organoid Medicine (CuSTOM) Cincinnati Children’s Hospital Medical Center)

  • Maciej Paszkowski-Rogacz

    (Technical University Dresden)

  • Janet Karpinski

    (Technical University Dresden)

  • Tobias Grass

    (Technical University Dresden
    Helmholtz Association)

  • Jan Sonntag

    (Technical University Dresden)

  • Paul Martin Schneider

    (Technical University Dresden)

  • Ceren Günes

    (Max Planck Institute for Molecular Biomedicine)

  • Jenna Hoersten

    (Technical University Dresden)

  • Lukas Theo Schmitt

    (Technical University Dresden)

  • Natalia Rodriguez-Muela

    (Helmholtz Association)

  • Ralf Knöfler

    (University Hospital Dresden)

  • Takanori Takebe

    (Center for Stem Cell and Organoid Medicine (CuSTOM) Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine
    Tokyo Medical and Dental University (TMDU))

  • Frank Buchholz

    (Technical University Dresden)

Abstract

Despite advances in nuclease-based genome editing technologies, correcting human disease-causing genomic inversions remains a challenge. Here, we describe the potential use of a recombinase-based system to correct the 140 kb inversion of the F8 gene frequently found in patients diagnosed with severe Hemophilia A. Employing substrate-linked directed molecular evolution, we develop a coupled heterodimeric recombinase system (RecF8) achieving 30% inversion of the target sequence in human tissue culture cells. Transient RecF8 treatment of endothelial cells, differentiated from patient-derived induced pluripotent stem cells (iPSCs) of a hemophilic donor, results in 12% correction of the inversion and restores Factor VIII mRNA expression. In this work, we present designer-recombinases as an efficient and specific means towards treatment of monogenic diseases caused by large gene inversions.

Suggested Citation

  • Felix Lansing & Liliya Mukhametzyanova & Teresa Rojo-Romanos & Kentaro Iwasawa & Masaki Kimura & Maciej Paszkowski-Rogacz & Janet Karpinski & Tobias Grass & Jan Sonntag & Paul Martin Schneider & Ceren, 2022. "Correction of a Factor VIII genomic inversion with designer-recombinases," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28080-7
    DOI: 10.1038/s41467-022-28080-7
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    Cited by:

    1. Lukas Theo Schmitt & Maciej Paszkowski-Rogacz & Florian Jug & Frank Buchholz, 2022. "Prediction of designer-recombinases for DNA editing with generative deep learning," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Charlotte Cautereels & Jolien Smets & Jonas De Saeger & Lloyd Cool & Yanmei Zhu & Anna Zimmermann & Jan Steensels & Anton Gorkovskiy & Thomas B. Jacobs & Kevin J. Verstrepen, 2024. "Orthogonal LoxPsym sites allow multiplexed site-specific recombination in prokaryotic and eukaryotic hosts," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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