期刊
CELL STEM CELL
卷 17, 期 2, 页码 213-220出版社
CELL PRESS
DOI: 10.1016/j.stem.2015.07.001
关键词
-
资金
- National Research Foundation of Korea (the Bio and Medical Technology Development Program) [2012M3A9B4028631, 2012M3A9C7050126]
- Korean Ministry of Health and Welfare [A120254]
- IBS [IBS-R021-D1]
- National Research Foundation of Korea [2012M3A9C7050139]
- Korea Health Promotion Institute [HI12C0205010014] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- Ministry of Science, ICT & Future Planning, Republic of Korea [IBS-R021-D1-2015-A00] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2012M3A9C7050126, 2012M3A9B4028631, 2012M3A9C7050139, 2015R1D1A4A01019667] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据