| Autor: |
Maciej Paszkowski-Rogacz, Frank Buchholz, Lukas Theo Schmitt, Takanori Takebe, Kentaro Iwasawa, Hoersten J, Masaki Kimura, Felix Lansing, Janet Karpinski, Rodriguez-Muela N, Grass T, Sonntag J, Günes C, Schneider Pm, Knöfler R, Rojo-Romanos T, Mukhametzyanova L |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.11.02.328013 |
| Popis: |
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 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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