Disease-specific pluripotent stem cells generated from patient somatic cells already provide a powerful approach to model human disease. The therapeutic potential of iPS cells has now been demonstrated by Raya et al who took somatic cells from Fanconi anemia (FA) patients and showed they could generate iPS cells and differentiated haematopoietic progenitors. Due to the genetic instability and apoptotic predisposition of FA cells, the somatic cells could only be reprogrammed after genetic correction. The iPS cells generated from genetically corrected somatic cells maintained a fully functional FA pathway and were shown to differentiate into all developmental lineages in vitro and form teratomas in vivo. Differentiation into erythroid and myeloid lineages was similar for iPS cells derived from FA patients and healthy individuals. The iPS-derived haematopoietic progenitors maintained the disease-free phenotype, which was demonstrated by a decreased hypersensitivity to DNA crosslinking agents similar to cells from healthy donors.
The study of Raya et al highlights the potential clinical relevance of iPS cells, however a few hurdles still need to be overcome before their application is fully realized. Reprogramming of somatic cells from FA patients first required genetic correction of the FA defect, highlighting a possible roadblock for iPS cell derivation from certain genetic diseases. The genetic correction was achieved by using viral vectors to introduce normal versions of the two FA genes into cells, but in the future homologous recombination may be used to correct genetic defects of patient-specific iPS cells. Indeed, a virus-free method for homologous recombination was recently optimized for human iPS cells by Zou et al who showed high efficiencies of homologous recombination-mediated targeting to either correct a chromosomally integrated mutant GFP gene or create a mutation in an endogenous PIG-A gene. In addition, while FA iPS cells successfully differentiated into haematopoietic progenitors with a functional FA pathway, no engraftment of human cells into mice could be observed, but this is likely due to current technical limitations. This is in contrast to an earlier study by Hanna et al that used mouse iPS cells differentiated into haematopoietic progenitors to treat sickle anemia. The authors showed they could reprogram mutant fibroblasts into iPS cells, repair the genetic deficit through homologous recombination, differentiate the repaired iPS cells into haematopoietic progenitors, and transplant these cells into a mouse model of human sickle cell anemia to correct the defect. Finally, efficient reprogramming required retroviruses to over-express transcription factors. Newer methods avoiding retroviral transduction exist (see blog “Human induced pluripotent stem cells generated by delivery of reprogramming proteins”), but these still need increased reprogramming efficiency before they are clinically relevant.
1. Raya, et al (2009) Nature
2. Hanna et al (2007) Science
3. Zou et al (2009) Cell Stem Cell