Genetic Correction of β-thalassemia Patient-Specific iPS Cells and Its Use in Improving Hemoglobin Production in Irradiated SCID Mice

Cell Res. 2012 Apr;22(4):637-48. doi: 10.1038/cr.2012.23. Epub 2012 Feb 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Child, Preschool
  • Disease Models, Animal
  • Fibroblasts / cytology
  • Genetic Therapy*
  • Hemoglobins / biosynthesis
  • Hemoglobins / genetics
  • Homologous Recombination
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / transplantation*
  • Mice
  • Mice, SCID
  • Mutation
  • beta-Globins / genetics*
  • beta-Thalassemia / genetics
  • beta-Thalassemia / therapy*

Substances

  • Hemoglobins
  • beta-Globins