Treatment of Sickle Cell Anemia Mouse Model with iPS Cells Generated from Autologous Skin

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Science (Impact Factor: 31.48). 01/2008; 318(5858):1920-3. DOI: 10.1126/science.1152092
Source: PubMed

ABSTRACT It has recently been demonstrated that mouse and human fibroblasts can be reprogrammed into an embryonic stem cell–like state
by introducing combinations of four transcription factors. However, the therapeutic potential of such induced pluripotent
stem (iPS) cells remained undefined. By using a humanized sickle cell anemia mouse model, we show that mice can be rescued
after transplantation with hematopoietic progenitors obtained in vitro from autologous iPS cells. This was achieved after
correction of the human sickle hemoglobin allele by gene-specific targeting. Our results provide proof of principle for using
transcription factor–induced reprogramming combined with gene and cell therapy for disease treatment in mice. The problems
associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered
for human therapy.

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    • "When autologous transplantation was performed using hematopoietic cells bearing the corrected sickle cell allele, the anemia phenotype was corrected (Hanna et al., 2007). Since that publication , gene correction has been performed in hiPSCs for several monogenetic blood disorders and tested in vitro and in xenografts (Simara et al., 2013). "
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    ABSTRACT: Human pluripotent stem cells have made a remarkable impact on science, technology and medicine by providing a potentially unlimited source of human cells for basic research and clinical applications. In recent years, knowledge gained from the study of human embryonic stem cells and mammalian somatic cell reprogramming has led to the routine production of human induced pluripotent stem cells (hiPSCs) in laboratories worldwide. hiPSCs show promise for use in transplantation, high throughput drug screening, "disease-in-a-dish" modeling, disease gene discovery, and gene therapy testing. This review will focus on the first application, beginning with a discussion of methods for producing retinal lineage cells that are lost in inherited and acquired forms of retinal degenerative disease. The selection of appropriate hiPSC-derived donor cell type(s) for transplantation will be discussed, as will the caveats and prerequisite steps to formulating a clinical Good Manufacturing Practice (cGMP) product for clinical trials.
    Experimental Eye Research 06/2014; 123. DOI:10.1016/j.exer.2013.12.001 · 3.02 Impact Factor
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    • "This technique, called gene targeting, has been successfully applied to cure sickle-cell anemia in a mouse model [17]. It has been suggested that statistically the two threefinger binding domains should enable the formation of the nuclease dimer only at the one desired location. "
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    ABSTRACT: Zinc finger nucleases (ZFNs) are associated with cell death and apoptosis by binding at countless undesired locations. This cytotoxicity is associated with the binding ability of engineered zinc finger domains to bind dissimilar DNA sequences with high affinity. In general, binding preferences of transcription factors are associated with significant degenerated diversity and complexity which convolutes the design and engineering of precise DNA binding domains. Evolutionary success of natural zinc finger proteins, however, evinces that nature created specific evolutionary traits and strategies, such as modularity and rank-specific recognition to cope with binding complexity that are critical for creating clinical viable tools to precisely modify the human genome. Our findings indicate preservation of general modularity and significant alteration of the rank-specific binding preferences of the three-finger binding domain of transcription factor SP1 when exchanging amino acids in the 2nd finger.
    04/2014; 2014:970595. DOI:10.1155/2014/970595
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    • "HSCs are among the most difficult cells to be differentiated from iPSCs [115], yet recent progress brings us closer to the dream of generating functional HSCs from iPSCs. Mouse repopulating-HSCs can be differentiated from mouse ESCs or iPSCs by overexpressing HOXB4 ectopically [117] [118], but long-term multi-lineage HSCs have not been obtained from ESCs or iPSCs without ectopic gene expression . This strategy did not work for human iPSCs, however, due to the differential effects of HOXB4 on cells from different species [64] [65]. "
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    ABSTRACT: Breakthroughs in cell fate conversion have made it possible to generate large quantities of patient-specific cells for regenerative medicine. Due to multiple advantages of peripheral blood cells over fibroblasts from skin biopsy, the use of blood mononuclear cells (MNCs) instead of skin fibroblasts will expedite reprogramming research and broaden the application of reprogramming technology. This review discusses current progress and challenges of generating induced pluripotent stem cells (iPSCs) from peripheral blood MNCs and of in vitro and in vivo conversion of blood cells into cells of therapeutic value, such as mesenchymal stem cells, neural cells and hepatocytes. An optimized design of lentiviral vectors is necessary to achieve high reprogramming efficiency of peripheral blood cells. More recently, non-integrating vectors such as Sendai virus and episomal vectors have been successfully employed in generating integration-free iPSCs and somatic stem cells.
    09/2013; 11(5). DOI:10.1016/j.gpb.2013.09.001
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