Correction of the sickle cell disease mutation in human hematopoietic stem/progenitor cells

被引：256

作者：

Hoban, Megan D. ^{[1
]}

Cost, Gregory J. ^{[2
]}

Mendel, Matthew C. ^{[2
]}

Romero, Zulema ^{[1
]}

Kaufman, Michael L. ^{[1
]}

Joglekar, Alok V. ^{[1
]}

Ho, Michelle ^{[1
]}

Lumaquin, Dianne ^{[1
]}

Gray, David ^{[1
]}

Lill, Georgia R. ^{[1
]}

Cooper, Aaron R. ^{[3
]}

Urbinati, Fabrizia ^{[1
]}

Senadheera, Shantha ^{[1
]}

Zhu, Allen ^{[2
]}

Liu, Pei-Qi ^{[2
]}

Paschon, David E. ^{[2
]}

Zhang, Lei ^{[2
]}

Rebar, Edward J. ^{[2
]}

Wilber, Andrew ^{[4
]}

Wang, Xiaoyan ^{[5
]}

Gregory, Philip D. ^{[2
]}

Holmes, Michael C. ^{[2
]}

Reik, Andreas ^{[2
]}

Hollis, Roger P. ^{[1
]}

Kohn, Donald B. ^{[1
,6
]}

机构：

[1] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA

[2] Sangamo BioSci Inc, Richmond, CA USA

[3] Univ Calif Los Angeles, Mol Biol Interdept PhD Program, Los Angeles, CA USA

[4] So Illinois Univ, Sch Med, Dept Med Microbiol Immunol & Cell Biol, Springfield, IL USA

[5] Univ Calif Los Angeles, Dept Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA

[6] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA USA

来源：

BLOOD | 2015年 / 125卷 / 17期

基金：

美国国家卫生研究院;

关键词：

ZINC-FINGER NUCLEASES; GLOBIN GENE-TRANSFER; DOUBLE-STRAND BREAKS; RED-BLOOD-CELLS; STEM-CELLS; LENTIVIRAL VECTORS; BETA-THALASSEMIA; BONE-MARROW; GENOME; THERAPY;

D O I：

10.1182/blood-2014-12-615948

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Sickle cell disease (SCD) is characterized by a single point mutation in the seventh codon of theb-globin gene. Site-specific correction of the sickle mutation in hematopoietic stem cells would allow for permanent production of normal red blood cells. Using zinc-finger nucleases (ZFNs) designed to flank the sickle mutation, we demonstrate efficient targeted cleavage at the beta-globin locus with minimal off-target modification. By codelivering a homologous donor template (either an integrase-defective lentiviral vector or a DNA oligonucleotide), high levels of gene modification were achieved in CD34(+) hematopoietic stem and progenitor cells. Modified cells maintained their ability to engraft NOD/SCID/IL2r gamma(null) mice and to produce cells from multiple lineages, although with a reduction in the modification levels relative to the in vitro samples. Importantly, ZFN-driven gene correction in CD34(+) cells from the bone marrow of patients with SCD resulted in the production of wild-type hemoglobin tetramers.

引用

页码：2597 / 2604

页数：8

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