Home > Publications Database > Correction of a Factor VIII genomic inversion with designer-recombinases. > print

001     163482
005     20230915090522.0
024 7 _ |a 10.1038/s41467-022-28080-7
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082 _ _ |a 500
100 1 _ |a Lansing, Felix
|0 0000-0001-9335-9749
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245 _ _ |a Correction of a Factor VIII genomic inversion with designer-recombinases.
260 _ _ |a [London]
|c 2022
|b Nature Publishing Group UK
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520 _ _ |a 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.
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650 _ 7 |a Recombinases
|2 NLM Chemicals
650 _ 7 |a Factor VIII
|0 9001-27-8
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650 _ 2 |a Amino Acid Sequence
|2 MeSH
650 _ 2 |a Base Sequence
|2 MeSH
650 _ 2 |a Cell Differentiation
|2 MeSH
650 _ 2 |a Chromosome Inversion: genetics
|2 MeSH
650 _ 2 |a Clone Cells
|2 MeSH
650 _ 2 |a Directed Molecular Evolution
|2 MeSH
650 _ 2 |a Endothelial Cells: cytology
|2 MeSH
650 _ 2 |a Endothelial Cells: metabolism
|2 MeSH
650 _ 2 |a Exons: genetics
|2 MeSH
650 _ 2 |a Factor VIII: genetics
|2 MeSH
650 _ 2 |a HEK293 Cells
|2 MeSH
650 _ 2 |a HeLa Cells
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Induced Pluripotent Stem Cells: metabolism
|2 MeSH
650 _ 2 |a Inverted Repeat Sequences: genetics
|2 MeSH
650 _ 2 |a Recombinases: metabolism
|2 MeSH
650 _ 2 |a Recombination, Genetic: genetics
|2 MeSH
650 _ 2 |a Substrate Specificity
|2 MeSH
650 _ 2 |a Whole Genome Sequencing
|2 MeSH
700 1 _ |a Mukhametzyanova, Liliya
|b 1
700 1 _ |a Rojo-Romanos, Teresa
|0 0000-0001-8660-9690
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700 1 _ |a Iwasawa, Kentaro
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700 1 _ |a Kimura, Masaki
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700 1 _ |a Paszkowski-Rogacz, Maciej
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700 1 _ |a Karpinski, Janet
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700 1 _ |a Grass, Tobias
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700 1 _ |a Sonntag, Jan
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700 1 _ |a Schneider, Paul Martin
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700 1 _ |a Günes, Ceren
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700 1 _ |a Hoersten, Jenna
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700 1 _ |a Schmitt, Lukas Theo
|0 0000-0002-5455-4901
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700 1 _ |a Rodriguez-Muela, Natalia
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700 1 _ |a Knöfler, Ralf
|b 14
700 1 _ |a Takebe, Takanori
|0 0000-0002-6989-3041
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700 1 _ |a Buchholz, Frank
|0 0000-0002-4577-3344
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773 _ _ |a 10.1038/s41467-022-28080-7
|g Vol. 13, no. 1, p. 422
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|t Nature Communications
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856 4 _ |y OpenAccess
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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