Journal Article

DZNE-2022-00242

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Correction of a Factor VIII genomic inversion with designer-recombinases.

Lansing, F. ; Mukhametzyanova, L. ; Rojo-Romanos, T. ; Iwasawa, K. ; Kimura, M. ; Paszkowski-Rogacz, M. ; Karpinski, J. ; Grass, T.DZNE* ; Sonntag, J. ; Schneider, P. M. ; Günes, C. ; Hoersten, J. ; Schmitt, L. T. ; Rodriguez-Muela, N.DZNE* ; Knöfler, R. ; Takebe, T. ; Buchholz, F.

2022
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-022-28080-7

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.

Keyword(s): Amino Acid Sequence (MeSH) ; Base Sequence (MeSH) ; Cell Differentiation (MeSH) ; Chromosome Inversion: genetics (MeSH) ; Clone Cells (MeSH) ; Directed Molecular Evolution (MeSH) ; Endothelial Cells: cytology (MeSH) ; Endothelial Cells: metabolism (MeSH) ; Exons: genetics (MeSH) ; Factor VIII: genetics (MeSH) ; HEK293 Cells (MeSH) ; HeLa Cells (MeSH) ; Humans (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Inverted Repeat Sequences: genetics (MeSH) ; Recombinases: metabolism (MeSH) ; Recombination, Genetic: genetics (MeSH) ; Substrate Specificity (MeSH) ; Whole Genome Sequencing (MeSH) ; Recombinases ; Factor VIII

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Contributing Institute(s):

1. Selective Neuronal Vulnerability in Neurodegenerative Diseases (AG Rodriguez-Muela)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2022

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