Genetic correction of β-thalassemia patient-specific iPS cells and its use in improving hemoglobin production in irradiated SCID mice.
The generation of induced pluripotent stem cells (iPSCs) from differentiated somatic cells by over-expression of several transcription factors has the potential to cure many genetic and degenerative diseases currently recalcitrant to traditional clinical approaches. One such genetic disease is β-thalassemia major (Cooley's anemia). This disease is caused by either a point mutation or the deletion of several nucleotides in the β-globin gene, and it threatens the lives of millions of people in China. In the present study, we successfully generated iPSCs from fibroblasts collected from a 2-year-old patient who was diagnosed with a homozygous 41/42 deletion in his β-globin gene. More importantly, we successfully corrected this genetic mutation in the β-thalassemia iPSCs by homologous recombination. Furthermore, transplantation of the genetically corrected iPSCs-derived hematopoietic progenitors into sub-lethally irradiated immune deficient SCID mice showed improved hemoglobin production compared with the uncorrected iPSCs. Moreover, the generation of human β-globin could be detected in the mice transplanted with corrected iPSCs-derived hematopietic progenitors. Our study provides strong evidence that iPSCs generated from a patient with a genetic disease can be corrected by homologous recombination and that the corrected iPSCs have potential clinical uses.
National Institute of Biological Sciences, Zhongguancun Life Science Park, Beijing, China.
Yixuan
Y
Wang
Chen-Guang
CG
Zheng
Yonghua
Y
Jiang
Jiqin
J
Zhang
Jiayu
J
Chen
Chao
C
Yao
Qingguo
Q
Zhao
Sheng
S
Liu
Ke
K
Chen
Juan
J
Du
Ze
Z
Yang
Shaorong
S
Gao
D000818:Animals; D002675:Child, Preschool; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology; D015316:Genetic Therapy; D006454:Hemoglobins / Q000096:biosynthesis / Q000235:genetics; D059765:Homologous Recombination; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics / Q000628:therapy*
D006454:Hemoglobins; D055544:beta-Globins