Modeling Human Severe Combined Immunodeficiency and Correction by CRISPR/Cas9-Enhanced Gene Targeting

被引:97
作者
Chang, Chia-Wei [1 ,5 ,6 ,10 ]
Lai, Yi-Shin [1 ,5 ,6 ,10 ]
Westin, Erik [1 ,5 ,6 ,10 ]
Khodadadi-Jamayran, Alireza [1 ,5 ,6 ,10 ]
Pawlik, Kevin M. [1 ,5 ,6 ,10 ]
Lamb, Lawrence S., Jr. [2 ,3 ,5 ,7 ,8 ,10 ]
Goldman, Frederick D. [4 ,5 ,9 ,10 ]
Townes, Tim M. [1 ,5 ,6 ,10 ]
机构
[1] Univ Alabama Birmingham, Sch Med, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Sch Med, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA
[3] Univ Alabama Birmingham, Sch Med, Cell Therapy Lab, Birmingham, AL 35294 USA
[4] Univ Alabama Birmingham, Sch Med, Dept Pediat, Div Hematol Oncol, Birmingham, AL 35294 USA
[5] Univ Alabama Birmingham, Sch Med, UAB Stem Cell Inst, Birmingham, AL 35294 USA
[6] Univ Alabama Birmingham, Sch Dent, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA
[7] Univ Alabama Birmingham, Sch Dent, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA
[8] Univ Alabama Birmingham, Sch Dent, Cell Therapy Lab, Birmingham, AL 35294 USA
[9] Univ Alabama Birmingham, Sch Dent, Dept Pediat, Div Hematol Oncol, Birmingham, AL 35294 USA
[10] Univ Alabama Birmingham, Sch Dent, UAB Stem Cell Inst, Birmingham, AL 35294 USA
关键词
T-CELL DEVELOPMENT; PLURIPOTENT STEM-CELLS; MICE LACKING JAK3; IN-VITRO; LYMPHOID DEVELOPMENT; BCL-2; EXPRESSION; DEFICIENT MICE; GAMMA-CHAIN; PAIRED-END; INDUCTION;
D O I
10.1016/j.celrep.2015.08.013
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Mutations of the Janus family kinase JAK3 gene cause severe combined immunodeficiency (SCID). JAK3 deficiency in humans is characterized by the absence of circulating T cells and natural killer (NK) cells with normal numbers of poorly functioning B cells (T-B+NK-). Using SCID patient-specific induced pluripotent stem cells (iPSCs) and a T cell in vitro differentiation system, we demonstrate a complete block in early T cell development of JAK3-deficient cells. Correction of the JAK3 mutation by CRISPR/Cas9-enhanced gene targeting restores normal T cell development, including the production of mature T cell populations with a broad T cell receptor (TCR) repertoire. Whole-genome sequencing of corrected cells demonstrates no CRISPR/ Cas9 off-target modifications. These studies describe an approach for the study of human lymphopoiesis and provide a foundation for gene correction therapy in humans with immunodeficiencies.
引用
收藏
页码:1668 / 1677
页数:10
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