Robust ZFN-mediated genome editing in adult hemophilic mice

被引：136

作者：

Anguela, Xavier M. ^{[1
,2
,3
]}

Sharma, Rajiv ^{[1
,2
]}

Doyon, Yannick ^{[4
,5
]}

Miller, Jeffrey C. ^{[6
]}

Li, Hojun ^{[1
,2
]}

Haurigot, Virginia ^{[1
,2
]}

Rohde, Michelle E. ^{[6
]}

Wong, Sunnie Y. ^{[6
]}

Davidson, Robert J. ^{[1
,2
]}

Zhou, Shangzhen ^{[1
,2
]}

Gregory, Philip D. ^{[6
]}

Holmes, Michael C. ^{[6
]}

High, Katherine A. ^{[1
,2
,3
]}

机构：

[1] Childrens Hosp Philadelphia, Div Hematol, Philadelphia, PA 19104 USA

[2] Childrens Hosp Philadelphia, Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA

[3] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA

[4] Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ, Canada

[5] Univ Laval, Fac Med, Dept Mol Med, Quebec City, PQ G1K 7P4, Canada

[6] Sangamo BioSci, Richmond, CA USA

来源：

BLOOD | 2013年 / 122卷 / 19期

基金：

美国国家卫生研究院;

关键词：

CELLS;

D O I：

10.1182/blood-2013-04-497354

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Monogenic diseases, including hemophilia, represent ideal targets for genome-editing approaches aimed at correcting a defective gene. Here we report that systemic adeno-associated virus (AAV) vector delivery of zinc finger nucleases (ZFNs) and corrective donor template to the predominantly quiescent livers of adult mice enables production of high levels of human factor IX in a murine model of hemophilia B. Further, we show that off-target cleavage can be substantially reduced while maintaining robust editing by using obligate heterodimeric ZFNs engineered to minimize unwanted cleavage attributable to homodimerization of the ZFNs. These results broaden the therapeutic potential of AAV/ZFN-mediated genome editing in the liver and could expand this strategy to other nonreplicating cell types.

引用

页码：3283 / 3287

页数：5

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