Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs

Guang Hui Liu; Keiichiro Suzuki; Jing Qu; Ignacio Sancho-Martinez; Fei Yi; Mo Li; Sachin Kumar; Emmanuel Nivet; Jessica Kim; Rupa Devi Soligalla; Ilir Dubova; April Goebl; Nongluk Plongthongkum; Ho Lim Fung; Kun Zhang; Jeanne F. Loring; Louise C. Laurent; Juan Carlos Izpisua Belmonte

doi:10.1016/j.stem.2011.04.019

Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs

Guang Hui Liu, Keiichiro Suzuki, Jing Qu, Ignacio Sancho-Martinez, Fei Yi, Mo Li, Sachin Kumar, Emmanuel Nivet, Jessica Kim, Rupa Devi Soligalla, Ilir Dubova, April Goebl, Nongluk Plongthongkum, Ho Lim Fung, Kun Zhang, Jeanne F. Loring, Louise C. Laurent, Juan Carlos Izpisua Belmonte

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

201 Scopus citations

Abstract

Combination of stem cell-based approaches with gene-editing technologies represents an attractive strategy for studying human disease and developing therapies. However, gene-editing methodologies described to date for human cells suffer from technical limitations including limited target gene size, low targeting efficiency at transcriptionally inactive loci, and off-target genetic effects that could hamper broad clinical application. To address these limitations, and as a proof of principle, we focused on homologous recombination-based gene correction of multiple mutations on lamin A (LMNA), which are associated with various degenerative diseases. We show that helper-dependent adenoviral vectors (HDAdVs) provide a highly efficient and safe method for correcting mutations in large genomic regions in human induced pluripotent stem cells and can also be effective in adult human mesenchymal stem cells. This type of approach could be used to generate genotype-matched cell lines for disease modeling and drug discovery and potentially also in therapeutics.

Original language	English (US)
Pages (from-to)	688-694
Number of pages	7
Journal	Cell Stem Cell
Volume	8
Issue number	6
DOIs	https://doi.org/10.1016/j.stem.2011.04.019
State	Published - Jun 3 2011
Externally published	Yes

Bibliographical note

Funding Information:
We would like to thank K. Mitani, P. Ng, and A. Lieber for kindly providing experimental materials, J. Karlseder, L. Gerace, M. Hetzer, and C. Rodriguez Esteban for helpful discussions, C. Lynch for running SNP genotyping arrays, M.C. Llach for karyotyping, M. Marti for teratoma analysis, Y. Xia and S.-L. Yang for technical help, and M. Schwarz for administrative help. G.-H.L. was partially supported by a CIRM grant (TG2-01158), and J.Q. was partially supported by an AFAR/Ellison Medical Foundation postdoctoral fellowship. E.N. was partially supported by a F.M. Kirby Foundation postdoctoral fellowship. L.C.L. is supported by NIH K12HD001259-11. The work by L.C.L. and J.F.L. was supported by CIRM TR1-01250. This study was supported by grants from DA025779 (K.Z.), the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi-Aventis, Ellison Medical Foundation, Helmsley Foundation, MICINN, and Fundacion Cellex (J.C.I.B.).

ASJC Scopus subject areas

Molecular Medicine
Genetics
Cell Biology

UN SDGs

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

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10.1016/j.stem.2011.04.019

Cite this

Liu, G. H., Suzuki, K., Qu, J., Sancho-Martinez, I., Yi, F., Li, M., Kumar, S., Nivet, E., Kim, J., Soligalla, R. D., Dubova, I., Goebl, A., Plongthongkum, N., Fung, H. L., Zhang, K., Loring, J. F., Laurent, L. C., & Izpisua Belmonte, J. C. (2011). Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell, 8(6), 688-694. https://doi.org/10.1016/j.stem.2011.04.019

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title = "Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs",

abstract = "Combination of stem cell-based approaches with gene-editing technologies represents an attractive strategy for studying human disease and developing therapies. However, gene-editing methodologies described to date for human cells suffer from technical limitations including limited target gene size, low targeting efficiency at transcriptionally inactive loci, and off-target genetic effects that could hamper broad clinical application. To address these limitations, and as a proof of principle, we focused on homologous recombination-based gene correction of multiple mutations on lamin A (LMNA), which are associated with various degenerative diseases. We show that helper-dependent adenoviral vectors (HDAdVs) provide a highly efficient and safe method for correcting mutations in large genomic regions in human induced pluripotent stem cells and can also be effective in adult human mesenchymal stem cells. This type of approach could be used to generate genotype-matched cell lines for disease modeling and drug discovery and potentially also in therapeutics.",

author = "Liu, {Guang Hui} and Keiichiro Suzuki and Jing Qu and Ignacio Sancho-Martinez and Fei Yi and Mo Li and Sachin Kumar and Emmanuel Nivet and Jessica Kim and Soligalla, {Rupa Devi} and Ilir Dubova and April Goebl and Nongluk Plongthongkum and Fung, {Ho Lim} and Kun Zhang and Loring, {Jeanne F.} and Laurent, {Louise C.} and {Izpisua Belmonte}, {Juan Carlos}",

note = "Funding Information: We would like to thank K. Mitani, P. Ng, and A. Lieber for kindly providing experimental materials, J. Karlseder, L. Gerace, M. Hetzer, and C. Rodriguez Esteban for helpful discussions, C. Lynch for running SNP genotyping arrays, M.C. Llach for karyotyping, M. Marti for teratoma analysis, Y. Xia and S.-L. Yang for technical help, and M. Schwarz for administrative help. G.-H.L. was partially supported by a CIRM grant (TG2-01158), and J.Q. was partially supported by an AFAR/Ellison Medical Foundation postdoctoral fellowship. E.N. was partially supported by a F.M. Kirby Foundation postdoctoral fellowship. L.C.L. is supported by NIH K12HD001259-11. The work by L.C.L. and J.F.L. was supported by CIRM TR1-01250. This study was supported by grants from DA025779 (K.Z.), the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi-Aventis, Ellison Medical Foundation, Helmsley Foundation, MICINN, and Fundacion Cellex (J.C.I.B.). ",

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month = jun,

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doi = "10.1016/j.stem.2011.04.019",

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Liu, GH, Suzuki, K, Qu, J, Sancho-Martinez, I, Yi, F, Li, M, Kumar, S, Nivet, E, Kim, J, Soligalla, RD, Dubova, I, Goebl, A, Plongthongkum, N, Fung, HL, Zhang, K, Loring, JF, Laurent, LC & Izpisua Belmonte, JC 2011, 'Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs', Cell Stem Cell, vol. 8, no. 6, pp. 688-694. https://doi.org/10.1016/j.stem.2011.04.019

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T1 - Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs

AU - Liu, Guang Hui

AU - Suzuki, Keiichiro

AU - Qu, Jing

AU - Sancho-Martinez, Ignacio

AU - Yi, Fei

AU - Li, Mo

AU - Kumar, Sachin

AU - Nivet, Emmanuel

AU - Kim, Jessica

AU - Soligalla, Rupa Devi

AU - Dubova, Ilir

AU - Goebl, April

AU - Plongthongkum, Nongluk

AU - Fung, Ho Lim

AU - Zhang, Kun

AU - Loring, Jeanne F.

AU - Laurent, Louise C.

AU - Izpisua Belmonte, Juan Carlos

N1 - Funding Information: We would like to thank K. Mitani, P. Ng, and A. Lieber for kindly providing experimental materials, J. Karlseder, L. Gerace, M. Hetzer, and C. Rodriguez Esteban for helpful discussions, C. Lynch for running SNP genotyping arrays, M.C. Llach for karyotyping, M. Marti for teratoma analysis, Y. Xia and S.-L. Yang for technical help, and M. Schwarz for administrative help. G.-H.L. was partially supported by a CIRM grant (TG2-01158), and J.Q. was partially supported by an AFAR/Ellison Medical Foundation postdoctoral fellowship. E.N. was partially supported by a F.M. Kirby Foundation postdoctoral fellowship. L.C.L. is supported by NIH K12HD001259-11. The work by L.C.L. and J.F.L. was supported by CIRM TR1-01250. This study was supported by grants from DA025779 (K.Z.), the G. Harold and Leila Y. Mathers Charitable Foundation, Sanofi-Aventis, Ellison Medical Foundation, Helmsley Foundation, MICINN, and Fundacion Cellex (J.C.I.B.).

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AB - Combination of stem cell-based approaches with gene-editing technologies represents an attractive strategy for studying human disease and developing therapies. However, gene-editing methodologies described to date for human cells suffer from technical limitations including limited target gene size, low targeting efficiency at transcriptionally inactive loci, and off-target genetic effects that could hamper broad clinical application. To address these limitations, and as a proof of principle, we focused on homologous recombination-based gene correction of multiple mutations on lamin A (LMNA), which are associated with various degenerative diseases. We show that helper-dependent adenoviral vectors (HDAdVs) provide a highly efficient and safe method for correcting mutations in large genomic regions in human induced pluripotent stem cells and can also be effective in adult human mesenchymal stem cells. This type of approach could be used to generate genotype-matched cell lines for disease modeling and drug discovery and potentially also in therapeutics.

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Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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