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

• Published in: Cell stem cell Vol. 16; no. 4; pp. 367 - 372
• Main Authors: Menon, Tushar, Firth, Amy L., Scripture-Adams, Deirdre D., Galic, Zoran, Qualls, Susan J., Gilmore, William B., Ke, Eugene, Singer, Oded, Anderson, Leif S., Bornzin, Alexander R., Alexander, Ian E., Zack, Jerome A., Verma, Inder M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.04.2015
• Subjects: Antigens, CD - metabolism; Bacterial Proteins - metabolism; Cell Differentiation - genetics; Cell Line; DNA Repair; DNA Repair Enzymes - metabolism; Genetic Therapy - methods; Humans; Immunotherapy, Adoptive; Induced Pluripotent Stem Cells - physiology; Induced Pluripotent Stem Cells - transplantation; Infant; Interleukin Receptor Common gamma Subunit - genetics; Killer Cells, Natural - physiology; Killer Cells, Natural - transplantation; Mutation - genetics; Precursor Cells, T-Lymphoid - physiology; Precursor Cells, T-Lymphoid - transplantation; Regeneration; Regenerative Medicine; X-Linked Combined Immunodeficiency Diseases - genetics; X-Linked Combined Immunodeficiency Diseases - therapy
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2015.02.005

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. [Display omitted] •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 Menon, Firth, and colleagues show that TALEN-mediated correction of a novel splice site mutation in the IL-2Rγ gene rescues defective development of mature NK cells from iPSCs derived from a SCID-X1 subject. They demonstrate correction of the aberrant splicing of the IL-2Rγ in T cell precursors.