Correction of a Factor VIII genomic inversion with designer-recombinases

Felix Lansing, Liliya Mukhametzyanova, Teresa Rojo-Romanos, Kentaro Iwasawa, Masaki Kimura, Maciej Paszkowski-Rogacz, Janet Karpinski, Tobias Grass, Jan Sonntag, Paul Martin Schneider, Ceren Günes, Jenna Hoersten, Lukas Theo Schmitt, Natalia Rodriguez-Muela, Ralf Knöfler, Takanori Takebe and Frank Buchholz ()
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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
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
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
Frank Buchholz: Technical University Dresden

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28080-7

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