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

Journal: 
Cell Stem Cell
Publication Year: 
2015
Authors: 
Tushar Menon
Amy L Firth
Deirdre D Scripture-Adams
Zoran Galic
Susan J Qualls
William B Gilmore
Eugene Ke
Oded Singer
Leif S Anderson
Alexander R Bornzin
Ian E Alexander
Jerome A Zack
Inder M Verma
PubMed link: 
25772073
Public Summary: 
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 is due to mutations in the gene encoding hormone receptor on white blood cells, leading to a lack of functional lymphocytes, a type of white blood cells. Viral gene therapy to replace the mutated gene carries the risk of inducing leukemia, so there is a need to explore alternative therapeutic options. We have utilized induced pluripotent stem cell (iPSC) technology and genome editing to generate patient-specific mutant and gene-corrected iPSC lines. While the patient-derived mutant iPSCs have the capacity to generate blood stem cells and other white blood cell types, only normal and gene-corrected iPSCs can additionally generate mature lymphocytes that produce the correct form of the hormone receptor. This study highlights the potential for the development of cell therapy for SCID-X1 patients.
Scientific 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-2Rgamma), 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-2Rgamma. This study highlights the potential for the development of autologous cell therapy for SCID-X1 subjects.