Generation of isogenic pluripotent stem cells differing exclusively at two early onset parkinson point mutations

Frank Soldner; Josée Laganière; Albert W. Cheng; Dirk Hockemeyer; Qing Gao; Raaji Alagappan; Vikram Khurana; Lawrence I. Golbe; Richard H. Myers; Susan Lindquist; Lei Zhang; Dmitry Guschin; Lauren K. Fong; B. Joseph Vu; Xiangdong Meng; Fyodor D. Urnov; Edward J. Rebar; Philip D. Gregory; H. Steve Zhang; Rudolf Jaenisch

doi:10.1016/j.cell.2011.06.019

Generation of isogenic pluripotent stem cells differing exclusively at two early onset parkinson point mutations

Frank Soldner, Josée Laganière, Albert W. Cheng, Dirk Hockemeyer, Qing Gao, Raaji Alagappan, Vikram Khurana, Lawrence I. Golbe, Richard H. Myers, Susan Lindquist, Lei Zhang, Dmitry Guschin, Lauren K. Fong, B. Joseph Vu, Xiangdong Meng, Fyodor D. Urnov, Edward J. Rebar, Philip D. Gregory, H. Steve Zhang, Rudolf Jaenisch

Research output: Contribution to journal › Article › peer-review

612 Scopus citations

Abstract

Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease, as well as a promising source for cell replacement therapies. One crucial limitation has been the inability to perform experiments under genetically defined conditions. This is particularly relevant for late age onset disorders in which in vitro phenotypes are predicted to be subtle and susceptible to significant effects of genetic background variations. By combining zinc finger nuclease (ZFN)-mediated genome editing and iPSC technology, we provide a generally applicable solution to this problem, generating sets of isogenic disease and control human pluripotent stem cells that differ exclusively at either of two susceptibility variants for Parkinson's disease by modifying the underlying point mutations in the α-synuclein gene. The robust capability to genetically correct disease-causing point mutations in patient-derived hiPSCs represents significant progress for basic biomedical research and an advance toward hiPSC-based cell replacement therapies.

Original language	English (US)
Pages (from-to)	318-331
Number of pages	14
Journal	Cell
Volume	146
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2011.06.019
State	Published - Jul 22 2011
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2011.06.019

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Soldner, F., Laganière, J., Cheng, A. W., Hockemeyer, D., Gao, Q., Alagappan, R., Khurana, V., Golbe, L. I., Myers, R. H., Lindquist, S., Zhang, L., Guschin, D., Fong, L. K., Vu, B. J., Meng, X., Urnov, F. D., Rebar, E. J., Gregory, P. D., Zhang, H. S., & Jaenisch, R. (2011). Generation of isogenic pluripotent stem cells differing exclusively at two early onset parkinson point mutations. Cell, 146(2), 318-331. https://doi.org/10.1016/j.cell.2011.06.019

Soldner, F, Laganière, J, Cheng, AW, Hockemeyer, D, Gao, Q, Alagappan, R, Khurana, V, Golbe, LI, Myers, RH, Lindquist, S, Zhang, L, Guschin, D, Fong, LK, Vu, BJ, Meng, X, Urnov, FD, Rebar, EJ, Gregory, PD, Zhang, HS & Jaenisch, R 2011, 'Generation of isogenic pluripotent stem cells differing exclusively at two early onset parkinson point mutations', Cell, vol. 146, no. 2, pp. 318-331. https://doi.org/10.1016/j.cell.2011.06.019

@article{707e35253a95412db171b65233db8d63,

title = "Generation of isogenic pluripotent stem cells differing exclusively at two early onset parkinson point mutations",

abstract = "Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease, as well as a promising source for cell replacement therapies. One crucial limitation has been the inability to perform experiments under genetically defined conditions. This is particularly relevant for late age onset disorders in which in vitro phenotypes are predicted to be subtle and susceptible to significant effects of genetic background variations. By combining zinc finger nuclease (ZFN)-mediated genome editing and iPSC technology, we provide a generally applicable solution to this problem, generating sets of isogenic disease and control human pluripotent stem cells that differ exclusively at either of two susceptibility variants for Parkinson's disease by modifying the underlying point mutations in the α-synuclein gene. The robust capability to genetically correct disease-causing point mutations in patient-derived hiPSCs represents significant progress for basic biomedical research and an advance toward hiPSC-based cell replacement therapies.",

author = "Frank Soldner and Jos{\'e}e Lagani{\`e}re and Cheng, {Albert W.} and Dirk Hockemeyer and Qing Gao and Raaji Alagappan and Vikram Khurana and Golbe, {Lawrence I.} and Myers, {Richard H.} and Susan Lindquist and Lei Zhang and Dmitry Guschin and Fong, {Lauren K.} and Vu, {B. Joseph} and Xiangdong Meng and Urnov, {Fyodor D.} and Rebar, {Edward J.} and Gregory, {Philip D.} and Zhang, {H. Steve} and Rudolf Jaenisch",

note = "Funding Information: We thank Ping Xu and Tenzin Lungjangwa for technical support and Jessica Dausman, Kibibi Ganz, Ruth Flannery, and Dongdong Fu for their help with animal husbandry and processing of teratomas. We would like to thank Tom Volkert and Jeong-Ah Kwon of the Whitehead Genome Technology Core for their help with the CNV analysis; Nicki Watson of the W.M. Keck Microscopy Facility for help with confocal microscopy; and Patti Wisniewski and Chad Araneo of the Whitehead Institute FACS facility for their help with cell sorting. We thank Gladys Dulay for construction of ZFN vectors and Elo Leung for computational analysis for the off-target study. We thank all of the members of the Jaenisch lab for helpful discussions and comments on the manuscript. R.J. was supported by NIH grants R01-CA084198 and R37-HD045022. This research was supported, in part, by a Collaborative Innovation Award from the Howard Hughes Medical Institute. R.J. is an adviser to Stemgent and a cofounder of Fate Therapeutics. D.H. is a Merck Fellow of the Life Sciences Research Foundation. J.L., L.K.F., L.Z., F.D.U., P.D.G., H.S.Z., D.J., B.J.V., X.M., and E.J.R. are full-time employees of Sangamo BioSciences, Inc. ",

year = "2011",

month = jul,

day = "22",

doi = "10.1016/j.cell.2011.06.019",

language = "English (US)",

volume = "146",

pages = "318--331",

journal = "Cell",

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TY - JOUR

T1 - Generation of isogenic pluripotent stem cells differing exclusively at two early onset parkinson point mutations

AU - Soldner, Frank

AU - Laganière, Josée

AU - Cheng, Albert W.

AU - Hockemeyer, Dirk

AU - Gao, Qing

AU - Alagappan, Raaji

AU - Khurana, Vikram

AU - Golbe, Lawrence I.

AU - Myers, Richard H.

AU - Lindquist, Susan

AU - Zhang, Lei

AU - Guschin, Dmitry

AU - Fong, Lauren K.

AU - Vu, B. Joseph

AU - Meng, Xiangdong

AU - Urnov, Fyodor D.

AU - Rebar, Edward J.

AU - Gregory, Philip D.

AU - Zhang, H. Steve

AU - Jaenisch, Rudolf

N1 - Funding Information: We thank Ping Xu and Tenzin Lungjangwa for technical support and Jessica Dausman, Kibibi Ganz, Ruth Flannery, and Dongdong Fu for their help with animal husbandry and processing of teratomas. We would like to thank Tom Volkert and Jeong-Ah Kwon of the Whitehead Genome Technology Core for their help with the CNV analysis; Nicki Watson of the W.M. Keck Microscopy Facility for help with confocal microscopy; and Patti Wisniewski and Chad Araneo of the Whitehead Institute FACS facility for their help with cell sorting. We thank Gladys Dulay for construction of ZFN vectors and Elo Leung for computational analysis for the off-target study. We thank all of the members of the Jaenisch lab for helpful discussions and comments on the manuscript. R.J. was supported by NIH grants R01-CA084198 and R37-HD045022. This research was supported, in part, by a Collaborative Innovation Award from the Howard Hughes Medical Institute. R.J. is an adviser to Stemgent and a cofounder of Fate Therapeutics. D.H. is a Merck Fellow of the Life Sciences Research Foundation. J.L., L.K.F., L.Z., F.D.U., P.D.G., H.S.Z., D.J., B.J.V., X.M., and E.J.R. are full-time employees of Sangamo BioSciences, Inc.

PY - 2011/7/22

Y1 - 2011/7/22

N2 - Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease, as well as a promising source for cell replacement therapies. One crucial limitation has been the inability to perform experiments under genetically defined conditions. This is particularly relevant for late age onset disorders in which in vitro phenotypes are predicted to be subtle and susceptible to significant effects of genetic background variations. By combining zinc finger nuclease (ZFN)-mediated genome editing and iPSC technology, we provide a generally applicable solution to this problem, generating sets of isogenic disease and control human pluripotent stem cells that differ exclusively at either of two susceptibility variants for Parkinson's disease by modifying the underlying point mutations in the α-synuclein gene. The robust capability to genetically correct disease-causing point mutations in patient-derived hiPSCs represents significant progress for basic biomedical research and an advance toward hiPSC-based cell replacement therapies.

AB - Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells provide a unique tool for the study of human disease, as well as a promising source for cell replacement therapies. One crucial limitation has been the inability to perform experiments under genetically defined conditions. This is particularly relevant for late age onset disorders in which in vitro phenotypes are predicted to be subtle and susceptible to significant effects of genetic background variations. By combining zinc finger nuclease (ZFN)-mediated genome editing and iPSC technology, we provide a generally applicable solution to this problem, generating sets of isogenic disease and control human pluripotent stem cells that differ exclusively at either of two susceptibility variants for Parkinson's disease by modifying the underlying point mutations in the α-synuclein gene. The robust capability to genetically correct disease-causing point mutations in patient-derived hiPSCs represents significant progress for basic biomedical research and an advance toward hiPSC-based cell replacement therapies.

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ER -

Generation of isogenic pluripotent stem cells differing exclusively at two early onset parkinson point mutations

Abstract

ASJC Scopus subject areas

UN SDGs

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