Lymphoid Regeneration from Gene-Corrected SCID-X1 Subject-Derived iPSCs

•A splice site mutation in IL-2Rγ was corrected at the endogenous locus using TALENs•Hematopoietic precursors and myeloid cells develop as normal from SCID-X1 iPSCs•Mature NK cells were generated from ESCs and iPSCs•Lymphoid differentiation recovered from only the gene-corrected SCID-X1 iPSCs

SummaryX-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.

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