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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents



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ID: 717273.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
Rescue of DNA-PK Signaling and T-Cell Differentiation by Targeted Genome Editing in a prkdc Deficient iPSC Disease Model
Authors:Rahman, S. H.; Kuehle, J.; Reimann, C.; Mlambo, T.; Alzubi, J.; Maeder, M. L.; Riedel, H.; Fisch, P.; Cantz, T.; Rudolph, C.; Mussolino, C.; Joung, J. K.; Schambach, A.; Cathomen, T.
Date of Publication (YYYY-MM-DD):2015-05
Title of Journal:PLoS Genetics
Volume:11
Issue / Number:5
Start Page:e1005239
Review Status:Internal review
Audience:Not Specified
Abstract / Description:In vitro disease modeling based on induced pluripotent stem cells (iPSCs) provides a powerful system to study cellular pathophysiology, especially in combination with targeted genome editing and protocols to differentiate iPSCs into affected cell types. In this study, we established zinc-finger nuclease-mediated genome editing in primary fibroblasts and iPSCs generated from a mouse model for radiosensitive severe combined immunodeficiency (RS-SCID), a rare disorder characterized by cellular sensitivity to radiation and the absence of lymphocytes due to impaired DNA-dependent protein kinase (DNA-PK) activity. Our results demonstrate that gene editing in RS-SCID fibroblasts rescued DNA-PK dependent signaling to overcome radiosensitivity. Furthermore, in vitro T-cell differentiation from iPSCs was employed to model the stage-specific T-cell maturation block induced by the disease causing mutation. Genetic correction of the RS-SCID iPSCs restored T-lymphocyte maturation, polyclonal V(D)J recombination of the T-cell receptor followed by successful beta-selection. In conclusion, we provide proof that iPSC-based in vitro T-cell differentiation is a valuable paradigm for SCID disease modeling, which can be utilized to investigate disorders of T-cell development and to validate gene therapy strategies for T-cell deficiencies. Moreover, this study emphasizes the significance of designer nucleases as a tool for generating isogenic disease models and their future role in producing autologous, genetically corrected transplants for various clinical applications.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany. Institute for Cell and Gene Therapy, University Medical Center Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany. Institute for Cell and Gene Therapy, University Medical Center Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany. Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America; Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America. Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany; Department of Biochemistry and Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia, United States of America. Institute of Pathology, University Medical Center Freiburg, Freiburg, Germany. Translational Hepatology and Stem Cell Biology, REBIRTH cluster of excellence, Hannover Medical School, Hannover, Germany. Institute for Cellular and Molecular Pathology, Hannover Medical School, Hannover, Germany. %W NLM %G eng
Identifiers:ISSN:1553-7390 %R 10.1371/journal.pgen.1005239 [ID No:1]
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