Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency.
In: Scientific reports, Jg. 8 (2018-05-29), Heft 1, S. 8214
Online
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Zugriff:
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.
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Molecular Evidence of Genome Editing in a Mouse Model of Immunodeficiency.
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Scientific reports, Jg. 8 (2018-05-29), Heft 1, S. 8214 |
Veröffentlichung: | London : Nature Publishing Group, copyright 2011-, 2018 |
Medientyp: | academicJournal |
ISSN: | 2045-2322 (electronic) |
DOI: | 10.1038/s41598-018-26439-9 |
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