Correction of a Factor VIII genomic inversion with designer-recombinases

Author:

Lansing FelixORCID,Mukhametzyanova LiliyaORCID,Rojo-Romanos TeresaORCID,Iwasawa KentaroORCID,Kimura Masaki,Paszkowski-Rogacz MaciejORCID,Karpinski JanetORCID,Grass Tobias,Sonntag Jan,Schneider Paul MartinORCID,Günes Ceren,Hoersten JennaORCID,Schmitt Lukas Theo,Rodriguez-Muela NataliaORCID,Knöfler Ralf,Takebe TakanoriORCID,Buchholz FrankORCID

Abstract

AbstractDespite 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 a 140 kb genomic inversion of the F8 gene, which is frequently found in patients diagnosed with severe Hemophilia A. Employing substrate-linked directed molecular evolution, we developed a fused 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, resulted in prominent correction of the inversion and restored Factor VIII mRNA expression. Our data suggests that designer-recombinases may represent efficient and specific means towards treatment of monogenic diseases caused by large gene inversions.

Publisher

Cold Spring Harbor Laboratory

Reference53 articles.

1. How the EUCERD Joint Action supported initiatives on Rare Diseases;Eur J Med Genet,2017

2. HuVarBase: A human variant database with comprehensive information at gene and protein levels;PLoS ONE,2019

3. Genome editing with engineered zinc finger nucleases

4. Genome Editing: Past, Present, and Future;Yale J Biol Med,2017

5. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors;Nature Biotechnology 1998 16:7,2020

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