Targeted gene addition in human CD34+ hematopoietic cells for correction of X-linked chronic granulomatous disease

被引：165

作者：

De Ravin, Suk See ^{[1
]}

Reik, Andreas ^{[2
]}

Liu, Pei-Qi ^{[2
]}

Li, Linhong ^{[3
]}

Wu, Xiaolin ^{[4
]}

Su, Ling ^{[4
]}

Raley, Castle ^{[4
]}

Theobald, Narda ^{[1
]}

Choi, Uimook ^{[1
]}

Song, Alexander H. ^{[2
]}

Chan, Andy ^{[2
]}

Pearl, Jocelynn R. ^{[2
]}

Paschon, David E. ^{[2
]}

Lee, Janet ^{[1
]}

Newcombe, Hannah ^{[1
]}

Koontz, Sherry ^{[1
]}

Sweeney, Colin ^{[1
]}

Shivak, David A. ^{[2
]}

Zarember, Kol A. ^{[1
]}

Peshwa, Madhusudan V. ^{[4
]}

Gregory, Philip D. ^{[2
,5
]}

Urnov, Fyodor D. ^{[2
]}

Malech, Harry L. ^{[1
]}

机构：

[1] NIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[2] Sangamo BioSci Inc, Richmond, CA USA

[3] MaxCyte Inc, Gaithersburg, MD USA

[4] Leidos Biomed Res Inc, Canc Res Technol Program, Frederick, MD USA

[5] Blubird Bio, Cambridge, MA USA

来源：

NATURE BIOTECHNOLOGY | 2016年 / 34卷 / 04期

基金：

美国国家卫生研究院;

关键词：

THERAPY; STEM; EXPRESSION; VECTORS; OXIDASE;

D O I：

10.1038/nbt.3513

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in similar to 15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases.

引用

页码：424 / +

页数：8

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