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Cell Stem Cell. 2015 Apr 2;16(4):367-72. doi: 10.1016/j.stem.2015.02.005. Epub 2015 Mar 12.

Lymphoid regeneration from gene-corrected SCID-X1 subject-derived iPSCs.

Author information

1
The Salk Institute of Biological Studies, Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
2
David Geffen School of Medicine at UCLA, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678; UCLA AIDS Institute, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678.
3
David Geffen School of Medicine at UCLA, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678; Broad Stem Cell Research Center, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678.
4
Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead, Wentworthville, NSW 2145, Australia.
5
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678; David Geffen School of Medicine at UCLA, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678; UCLA AIDS Institute, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678; Broad Stem Cell Research Center, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678.
6
The Salk Institute of Biological Studies, Laboratory of Genetics, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: verma@salk.edu.

Abstract

X-linked Severe Combined Immunodeficiency (SCID-X1) is a genetic disease that leaves newborns at high risk of serious infection and a predicted life span of less than 1 year in the absence of a matched bone marrow donor. The disease pathogenesis is due to mutations in the gene encoding the Interleukin-2 receptor gamma chain (IL-2Rγ), leading to a lack of functional lymphocytes. With the leukemogenic concerns of viral gene therapy there is a need to explore alternative therapeutic options. We have utilized induced pluripotent stem cell (iPSC) technology and genome editing mediated by TALENs to generate isogenic subject-specific mutant and gene-corrected iPSC lines. While the subject-derived mutant iPSCs have the capacity to generate hematopoietic precursors and myeloid cells, only wild-type and gene-corrected iPSCs can additionally generate mature NK cells and T cell precursors expressing the correctly spliced IL-2Rγ. This study highlights the potential for the development of autologous cell therapy for SCID-X1 subjects.

PMID:
25772073
PMCID:
PMC4545662
DOI:
10.1016/j.stem.2015.02.005
[Indexed for MEDLINE]
Free PMC Article

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