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Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9

Title
Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9
Author
배상수
Keywords
RNA-GUIDED ENDONUCLEASES; ZINC-FINGER NUCLEASES; OFF-TARGET CLEAVAGE; STEM-CELL CLONES; ENDOTHELIAL-CELLS; CAS NUCLEASES; SPECIFICITY; TALENS; CRISPR/CAS9; VECTORS
Issue Date
2015-08
Publisher
CELL PRESS
Citation
CELL STEM CELL, v. 17, NO 2, Page. 213-220
Abstract
Hemophilia A is an X-linked genetic disorder caused by mutations in the F8 gene, which encodes the blood coagulation factor VIII. Almost half of all severe hemophilia A cases result from two gross (140-kbp or 600-kbp) chromosomal inversions that involve introns 1 and 22 of the F8 gene, respectively. We derived induced pluripotent stem cells (iPSCs) from patients with these inversion genotypes and used CRISPR-Cas9 nucleases to revert these chromosomal segments back to the WT situation. We isolated inversion-corrected iPSCs with frequencies of up to 6.7% without detectable off-target mutations based on whole-genome sequencing or targeted deep sequencing. Endothelial cells differentiated from corrected iPSCs expressed the F8 gene and functionally rescued factor VIII deficiency in an otherwise lethal mouse model of hemophilia. Our results therefore provide a proof of principle for functional correction of large chromosomal rearrangements in patient-derived iPSCs and suggest potential therapeutic applications.
URI
http://www.sciencedirect.com/science/article/pii/S1934590915003008http://hdl.handle.net/20.500.11754/26952
ISSN
1934-5909; 1875-9777
DOI
10.1016/j.stem.2015.07.001
Appears in Collections:
COLLEGE OF NATURAL SCIENCES[S](자연과학대학) > CHEMISTRY(화학과) > Articles
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