Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells

被引：484

作者：

Yusa, Kosuke ^{[1
]}

Rashid, S. Tamir ^{[2
,3
]}

Strick-Marchand, Helene ^{[4
,5
]}

Varela, Ignacio ^{[6
]}

Liu, Pei-Qi ^{[7
]}

Paschon, David E. ^{[7
]}

Miranda, Elena ^{[3
,8
]}

Ordonez, Adriana ^{[3
]}

Hannan, Nicholas R. F. ^{[2
]}

Rouhani, Foad J. ^{[1
,2
]}

Darche, Sylvie ^{[4
,5
]}

Alexander, Graeme ^{[9
]}

Marciniak, Stefan J. ^{[3
]}

Fusaki, Noemi ^{[10
,11
]}

Hasegawa, Mamoru ^{[10
]}

Holmes, Michael C. ^{[7
]}

Di Santo, James P. ^{[4
,5
]}

Lomas, David A. ^{[3
]}

Bradley, Allan ^{[1
]}

Vallier, Ludovic ^{[2
]}

机构：

[1] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[2] Univ Cambridge, Anne McLaren Lab Regenerat Med, Dept Surg, Cambridge CB2 0SZ, England

[3] Univ Cambridge, Dept Med, Cambridge Inst Med Res, Cambridge CB0 2XY, England

[4] Inst Pasteur, Innate Immun Unit, F-75724 Paris, France

[5] INSERM, U668, F-75724 Paris, France

[6] CSIC UC SODERCAN, Inst Biomed & Biotecnol Cantabria, Santander 39011, Spain

[7] Sangamo BioSci Inc, Richmond, CA 94804 USA

[8] Univ Roma La Sapienza, Dept Biol Biotecnol Charles Darwin, I-00185 Rome, Italy

[9] Cambridge Univ Hosp NHS Trust, Dept Med, Div Gastroenterol & Hepatol, Cambridge CB2 2QQ, England

[10] DNAVEC Corp, Tsukuba, Ibaraki 3002611, Japan

[11] JST, PRESTO, Saitama 3320012, Japan

来源：

NATURE | 2011年 / 478卷 / 7369期

基金：

日本学术振兴会; 日本科学技术振兴机构; 英国惠康基金;

关键词：

EFFICIENT; GENERATION; PIGGYBAC; GENOME; INDUCTION; COMPLEX;

D O I：

10.1038/nature10424

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：

Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders(1-4). However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications(3,5). The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome(6). Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs)(7) and piggyBac(8,9) technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the alpha(1)-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for alpha(1)-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies.

引用

页码：391 / +

页数：6

共 36 条

[1] A map of human genome variation from population-scale sequencing [J].

Altshuler, David ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Collins, Francis S. ;

De la Vega, Francisco M. ;

Donnelly, Peter ;

Egholm, Michael ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Knoppers, Bartha M. ;

Lander, Eric S. ;

Lehrach, Hans ;

Mardis, Elaine R. ;

McVean, Gil A. ;

Nickerson, DebbieA. ;

Peltonen, Leena ;

Schafer, Alan J. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Deiros, David ;

Metzker, Mike ;

Muzny, Donna ;

Reid, Jeff ;

Wheeler, David ;

Wang, Jun ;

Li, Jingxiang ;

Jian, Min ;

Li, Guoqing ;

Li, Ruiqiang ;

Liang, Huiqing ;

Tian, Geng ;

Wang, Bo ;

Wang, Jian ;

Wang, Wei ;

Yang, Huanming ;

Zhang, Xiuqing ;

Zheng, Huisong ;

Lander, Eric S. ;

Altshuler, David L. ;

Ambrogio, Lauren ;

Bloom, Toby ;

Cibulskis, Kristian ;

Fennell, Tim J. ;

Gabriel, Stacey B. .

NATURE, 2010, 467 (7319) :1061-1073

[2] Adaptation to culture of human embryonic stem cells and oncogenesis in vivo [J].

Baker, Duncan E. C. ;

Harrison, Neil J. ;

Maltby, Edna ;

Smith, Kath ;

Moore, Harry D. ;

Shaw, Pamela J. ;

Heath, Paul R. ;

Holden, Hazel ;

Andrews, Peter W. .

NATURE BIOTECHNOLOGY, 2007, 25 (02) :207-215

[3] Engineering polydactyl zinc-finger transcription factors [J].

Beerli, RR ;

Barbas, CF .

NATURE BIOTECHNOLOGY, 2002, 20 (02) :135-141

[4] Generation of an inducible and optimized piggyBac transposon systemy [J].

Cadinanos, Juan ;

Bradley, Allan .

NUCLEIC ACIDS RESEARCH, 2007, 35 (12)

[5] The challenge of immunogenicity in the quest for induced pluripotency [J].

Fairchild, Paul J. .

NATURE REVIEWS IMMUNOLOGY, 2010, 10 (12) :868-875

[6] Precise excision of TTAA-specific lepidopteran transposons piggyBac(IFP2) and tagalong (TFP3) from the baculovirus genome in cell lines from two species of Lepidoptera [J].

Fraser, MJ ;

Coszczon, T ;

Elick, T ;

Bauser, C .

INSECT MOLECULAR BIOLOGY, 1996, 5 (02) :141-151

[7] Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome [J].

Fusaki, Noemi ;

Ban, Hiroshi ;

Nishiyama, Akiyo ;

Saeki, Koichi ;

Hasegawa, Mamoru .

PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES, 2009, 85 (08) :348-362

[8] Conformational Pathology of the Serpins: Themes, Variations, and Therapeutic Strategies [J].

Gooptu, Bibek ;

Lomas, David A. .

ANNUAL REVIEW OF BIOCHEMISTRY, 2009, 78 :147-176

[9]

Guschin DY, 2010, METHODS MOL BIOL, V649, P247, DOI 10.1007/978-1-60761-753-2_15

[10] Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin [J].

Hanna, Jacob ;

Wernig, Marius ;

Markoulaki, Styliani ;

Sun, Chiao-Wang ;

Meissner, Alexander ;

Cassady, John P. ;

Beard, Caroline ;

Brambrink, Tobias ;

Wu, Li-Chen ;

Townes, Tim M. ;

Jaenisch, Rudolf .

SCIENCE, 2007, 318 (5858) :1920-1923

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