Targeted inversion and reversion of the blood coagulation factor 8 gene in human iPS cells using TALENs

Chul Yong Park, Jungeun Kim, Jiyeon Kweon, Jeong Sang Son, Jae Souk Lee, Jeong Eun Yoo, Sung Rae Cho, Jong Hoon Kim, Jin Soo Kim, Dong Wook Kim

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Hemophilia A, one of the most common genetic bleeding disorders, is caused by various mutations in the blood coagulation factor VIII (F8) gene. Among the genotypes that result in hemophilia A, two different types of chromosomal inversions that involve a portion of the F8 gene are most frequent, accounting for almost half of all severe hemophilia A cases. In this study, we used a transcription activator-like effector nuclease (TALEN) pair to invert a 140-kbp chromosomal segment that spans the portion of the F8 gene in human induced pluripotent stem cells (iPSCs) to create a hemophilia A model cell line. In addition, we reverted the inverted segment back to its normal orientation in the hemophilia model iPSCs using the same TALEN pair. Importantly, we detected the F8 mRNA in cells derived from the reverted iPSCs lines, but not in those derived from the clones with the inverted segment. Thus, we showed that TALENs can be used both for creating disease models associated with chromosomal rearrangements in iPSCs and for correcting genetic defects caused by chromosomal inversions. This strategy provides an iPSC-based novel therapeutic option for the treatment of hemophilia A and other genetic diseases caused by chromosomal inversions.

Original languageEnglish
Pages (from-to)9253-9258
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number25
DOIs
Publication statusPublished - 2014 Jun 24

All Science Journal Classification (ASJC) codes

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