Targeted Correction and Restored Function of the CFTR Gene in Cystic Fibrosis Induced Pluripotent Stem Cells

被引：150

作者：

Crane, Ana M. ^{[1
]}

Kramer, Philipp ^{[1
]}

Bui, Jacquelin H. ^{[1
]}

Chung, Wook Joon ^{[2
]}

Li, Xuan Shirley ^{[1
]}

Gonzalez-Garay, Manuel L. ^{[3
]}

Hawkins, Finn ^{[4
,5
]}

Liao, Wei ^{[1
]}

Mora, Daniela ^{[1
]}

Choi, Sangbum ^{[6
]}

Wang, Jianbin ^{[7
]}

Sun, Helena C. ^{[7
]}

Paschon, David E. ^{[7
]}

Guschin, Dmitry Y. ^{[7
]}

Gregory, Philip D. ^{[7
]}

Kotton, Darrell N. ^{[4
,5
]}

Holmes, Michael C. ^{[7
]}

Sorscher, Eric J. ^{[2
]}

Davis, Brian R. ^{[1
]}

机构：

[1] Univ Texas Hlth Sci Ctr Houston, Ctr Stem Cell & Regenerat Med, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA

[2] Univ Alabama Birmingham, Gregory Fleming James Cyst Fibrosis Res Ctr, Birmingham, AL 35294 USA

[3] Univ Texas Hlth Sci Ctr Houston, Ctr Mol Imaging, Brown Fdn, Inst Mol Med, Houston, TX 77030 USA

[4] Boston Univ, Ctr Regenerat Med, Boston, MA 02118 USA

[5] Boston Med Ctr, Boston, MA 02118 USA

[6] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Div Clin & Translat Sci, Houston, TX 77030 USA

[7] Sangamo BioSci Inc, Richmond, CA 94804 USA

来源：

STEM CELL REPORTS | 2015年 / 4卷 / 04期

关键词：

ZINC-FINGER NUCLEASES; AIRWAY EPITHELIA; LUNG; GENERATION; IDENTIFICATION; PROGENITORS; REGIONS;

D O I：

10.1016/j.stemcr.2015.02.005

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Recently developed reprogramming and genome editing technologies make possible the derivation of corrected patient-specific pluripotent stem cell sources-potentially useful for the development of new therapeutic approaches. Starting with skin fibroblasts from patients diagnosed with cystic fibrosis, we derived and characterized induced pluripotent stem cell (iPSC) lines. We then utilized zinc-finger nucleases (ZFNs), designed to target the endogenous CFTR gene, to mediate correction of the inherited genetic mutation in these patient-derived lines via homology-directed repair (HDR). We observed an exquisitely sensitive, homology-dependent preference for targeting one CFTR allele versus the other. The corrected cystic fibrosis iPSCs, when induced to differentiate in vitro, expressed the corrected CFTR gene; importantly, CFTR correction resulted in restored expression of the mature CFTR glycoprotein and restoration of CFTR chloride channel function in iPSC-derived epithelial cells.

引用

页码：569 / 577

页数：9

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