Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia

被引：88

作者：

Mettananda, Sachith ^{[1
,2
]}

Fisher, Chris A. ^{[1
]}

Hay, Deborah ^{[1
]}

Badat, Mohsin ^{[1
]}

Quek, Lynn ^{[1
]}

Clark, Kevin ^{[3
]}

Hublitz, Philip ^{[3
]}

Downes, Damien ^{[1
]}

Kerry, Jon ^{[1
]}

Gosden, Matthew ^{[1
]}

Telenius, Jelena ^{[1
]}

Sloane-Stanley, Jackie A. ^{[1
]}

Faustino, Paula ^{[4
,5
]}

Coelho, Andreia ^{[4
]}

Doondeea, Jessica ^{[1
]}

Usukhbayar, Batchimeg ^{[1
]}

Sopp, Paul ^{[3
]}

Sharpe, Jacqueline A. ^{[1
]}

Hughes, Jim R. ^{[1
]}

Vyas, Paresh ^{[1
,6
]}

Gibbons, Richard J. ^{[1
]}

Higgs, Douglas R. ^{[1
,6
]}

机构：

[1] Univ Oxford, Weatherall Inst Mol Med, MRC, Mol Hematol Unit, Oxford OX3 9DS, England

[2] Univ Kelaniya, Fac Med, Dept Paediat, Ragama 11010, Sri Lanka

[3] Univ Oxford, MRC, Weatherall Inst Mol Med, Oxford OX3 9DS, England

[4] Natl Inst Hlth Dr Ricardo Jorge, Human Genet Dept, Av Padre Cruz, P-1649016 Lisbon, Portugal

[5] Univ Lisbon, Fac Med, Inst Environm Hlth, Av Prof Egas Moniz, P-1649028 Lisbon, Portugal

[6] Oxford Univ Hosp, Hlth Res Biomed Res Ctr, Oxford Natl Inst, Blood Theme, Oxford OX3 9DU, England

来源：

NATURE COMMUNICATIONS | 2017年 / 8卷

基金：

英国医学研究理事会;

关键词：

GENOME; EXPRESSION; DELETION; THERAPY; TARGET;

D O I：

10.1038/s41467-017-00479-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

beta-Thalassemia is one of the most common inherited anemias, with no effective cure for most patients. The pathophysiology reflects an imbalance between alpha- and beta-globin chains with an excess of free alpha-globin chains causing ineffective erythropoiesis and hemolysis. When alpha-thalassemia is co-inherited with beta-thalassemia, excess free alpha-globin chains are reduced significantly ameliorating the clinical severity. Here we demonstrate the use of CRISPR/Cas9 genome editing of primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes the MCS-R2 alpha-globin enhancer and causes a-thalassemia. When edited CD34+ cells are differentiated into erythroid cells, we observe the expected reduction in alpha-globin expression and a correction of the pathologic globin chain imbalance in cells from patients with beta-thalassemia. Xenograft assays show that a proportion of the edited CD34+ cells are long-term repopulating hematopoietic stem cells, demonstrating the potential of this approach for translation into a therapy for beta-thalassemia.

引用

页数：11

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