Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency. / Abdul-Razak, H. H.; Rocca, C. J.; Howe, S. J.; Alonso-Ferrero, M. E.; Wang, J.; Gabriel, R.; Bartholomae, C. C.; Gan, C. H.V.; Garín, M. I.; Roberts, A.; Blundell, M. P.; Prakash, V.; Molina-Estevez, F. J.; Pantoglou, J.; Guenechea, G.; Holmes, M. C.; Gregory, P. D.; Kinnon, C.; Von Kalle, C.; Schmidt, M.; Bueren, J. A.; Thrasher, A. J.; Yáñez-Muñoz, R. J.

In: Scientific Reports, Vol. 8, 8214, 29.05.2018, p. 1-13.

Research output: Contribution to journalArticle

Published

Standard

Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency. / Abdul-Razak, H. H.; Rocca, C. J.; Howe, S. J.; Alonso-Ferrero, M. E.; Wang, J.; Gabriel, R.; Bartholomae, C. C.; Gan, C. H.V.; Garín, M. I.; Roberts, A.; Blundell, M. P.; Prakash, V.; Molina-Estevez, F. J.; Pantoglou, J.; Guenechea, G.; Holmes, M. C.; Gregory, P. D.; Kinnon, C.; Von Kalle, C.; Schmidt, M.; Bueren, J. A.; Thrasher, A. J.; Yáñez-Muñoz, R. J.

In: Scientific Reports, Vol. 8, 8214, 29.05.2018, p. 1-13.

Research output: Contribution to journalArticle

Harvard

Abdul-Razak, HH, Rocca, CJ, Howe, SJ, Alonso-Ferrero, ME, Wang, J, Gabriel, R, Bartholomae, CC, Gan, CHV, Garín, MI, Roberts, A, Blundell, MP, Prakash, V, Molina-Estevez, FJ, Pantoglou, J, Guenechea, G, Holmes, MC, Gregory, PD, Kinnon, C, Von Kalle, C, Schmidt, M, Bueren, JA, Thrasher, AJ & Yáñez-Muñoz, RJ 2018, 'Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency', Scientific Reports, vol. 8, 8214, pp. 1-13. https://doi.org/10.1038/s41598-018-26439-9

APA

Vancouver

Author

Abdul-Razak, H. H. ; Rocca, C. J. ; Howe, S. J. ; Alonso-Ferrero, M. E. ; Wang, J. ; Gabriel, R. ; Bartholomae, C. C. ; Gan, C. H.V. ; Garín, M. I. ; Roberts, A. ; Blundell, M. P. ; Prakash, V. ; Molina-Estevez, F. J. ; Pantoglou, J. ; Guenechea, G. ; Holmes, M. C. ; Gregory, P. D. ; Kinnon, C. ; Von Kalle, C. ; Schmidt, M. ; Bueren, J. A. ; Thrasher, A. J. ; Yáñez-Muñoz, R. J. / Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency. In: Scientific Reports. 2018 ; Vol. 8. pp. 1-13.

BibTeX

@article{e7fa630c1914458a9ec3893fe7de9c22,
title = "Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency",
abstract = "Genome editing is the introduction of directed modifications in the genome, a process boosted to therapeutic levels by designer nucleases. Building on the experience of ex vivo gene therapy for severe combined immunodeficiencies, it is likely that genome editing of haematopoietic stem/progenitor cells (HSPC) for correction of inherited blood diseases will be an early clinical application. We show molecular evidence of gene correction in a mouse model of primary immunodeficiency. In vitro experiments in DNA-dependent protein kinase catalytic subunit severe combined immunodeficiency (Prkdc scid) fibroblasts using designed zinc finger nucleases (ZFN) and a repair template demonstrated molecular and functional correction of the defect. Following transplantation of ex vivo gene-edited Prkdc scid HSPC, some of the recipient animals carried the expected genomic signature of ZFN-driven gene correction. In some primary and secondary transplant recipients we detected double-positive CD4/CD8 T-cells in thymus and single-positive T-cells in blood, but no other evidence of immune reconstitution. However, the leakiness of this model is a confounding factor for the interpretation of the possible T-cell reconstitution. Our results provide support for the feasibility of rescuing inherited blood disease by ex vivo genome editing followed by transplantation, and highlight some of the challenges.",
author = "Abdul-Razak, {H. H.} and Rocca, {C. J.} and Howe, {S. J.} and Alonso-Ferrero, {M. E.} and J. Wang and R. Gabriel and Bartholomae, {C. C.} and Gan, {C. H.V.} and Gar{\'i}n, {M. I.} and A. Roberts and Blundell, {M. P.} and V. Prakash and Molina-Estevez, {F. J.} and J. Pantoglou and G. Guenechea and Holmes, {M. C.} and Gregory, {P. D.} and C. Kinnon and {Von Kalle}, C. and M. Schmidt and Bueren, {J. A.} and Thrasher, {A. J.} and Y{\'a}{\~n}ez-Mu{\~n}oz, {R. J.}",
year = "2018",
month = "5",
day = "29",
doi = "10.1038/s41598-018-26439-9",
language = "English",
volume = "8",
pages = "1--13",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

RIS

TY - JOUR

T1 - Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency

AU - Abdul-Razak, H. H.

AU - Rocca, C. J.

AU - Howe, S. J.

AU - Alonso-Ferrero, M. E.

AU - Wang, J.

AU - Gabriel, R.

AU - Bartholomae, C. C.

AU - Gan, C. H.V.

AU - Garín, M. I.

AU - Roberts, A.

AU - Blundell, M. P.

AU - Prakash, V.

AU - Molina-Estevez, F. J.

AU - Pantoglou, J.

AU - Guenechea, G.

AU - Holmes, M. C.

AU - Gregory, P. D.

AU - Kinnon, C.

AU - Von Kalle, C.

AU - Schmidt, M.

AU - Bueren, J. A.

AU - Thrasher, A. J.

AU - Yáñez-Muñoz, R. J.

PY - 2018/5/29

Y1 - 2018/5/29

N2 - Genome editing is the introduction of directed modifications in the genome, a process boosted to therapeutic levels by designer nucleases. Building on the experience of ex vivo gene therapy for severe combined immunodeficiencies, it is likely that genome editing of haematopoietic stem/progenitor cells (HSPC) for correction of inherited blood diseases will be an early clinical application. We show molecular evidence of gene correction in a mouse model of primary immunodeficiency. In vitro experiments in DNA-dependent protein kinase catalytic subunit severe combined immunodeficiency (Prkdc scid) fibroblasts using designed zinc finger nucleases (ZFN) and a repair template demonstrated molecular and functional correction of the defect. Following transplantation of ex vivo gene-edited Prkdc scid HSPC, some of the recipient animals carried the expected genomic signature of ZFN-driven gene correction. In some primary and secondary transplant recipients we detected double-positive CD4/CD8 T-cells in thymus and single-positive T-cells in blood, but no other evidence of immune reconstitution. However, the leakiness of this model is a confounding factor for the interpretation of the possible T-cell reconstitution. Our results provide support for the feasibility of rescuing inherited blood disease by ex vivo genome editing followed by transplantation, and highlight some of the challenges.

AB - Genome editing is the introduction of directed modifications in the genome, a process boosted to therapeutic levels by designer nucleases. Building on the experience of ex vivo gene therapy for severe combined immunodeficiencies, it is likely that genome editing of haematopoietic stem/progenitor cells (HSPC) for correction of inherited blood diseases will be an early clinical application. We show molecular evidence of gene correction in a mouse model of primary immunodeficiency. In vitro experiments in DNA-dependent protein kinase catalytic subunit severe combined immunodeficiency (Prkdc scid) fibroblasts using designed zinc finger nucleases (ZFN) and a repair template demonstrated molecular and functional correction of the defect. Following transplantation of ex vivo gene-edited Prkdc scid HSPC, some of the recipient animals carried the expected genomic signature of ZFN-driven gene correction. In some primary and secondary transplant recipients we detected double-positive CD4/CD8 T-cells in thymus and single-positive T-cells in blood, but no other evidence of immune reconstitution. However, the leakiness of this model is a confounding factor for the interpretation of the possible T-cell reconstitution. Our results provide support for the feasibility of rescuing inherited blood disease by ex vivo genome editing followed by transplantation, and highlight some of the challenges.

UR - http://www.scopus.com/inward/record.url?scp=85047857092&partnerID=8YFLogxK

U2 - 10.1038/s41598-018-26439-9

DO - 10.1038/s41598-018-26439-9

M3 - Article

VL - 8

SP - 1

EP - 13

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 8214

ER -