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

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Title
Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9
Author(s)
Chul-Yong Park; Duk Hyoung Kim; Jeong Sang Son; Jin Jea Sung; Jaehun Lee; Sangsu Bae; Jong-Hoon Kim; Dong-Wook Kim; Jin-Soo Kim
Publication Date
2015-08
Journal
CELL STEM CELL, v.17, no.2, pp.213 - 220
Publisher
CELL PRESS
Abstract
Summary 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. © 2015 Elsevier Inc
URI
https://pr.ibs.re.kr/handle/8788114/1925
ISSN
1934-5909
Appears in Collections:
Center for Genome Engineering(유전체 교정 연구단) > Journal Papers (저널논문)
Files in This Item:
2015_Cell Stem Cell.pdfDownload

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