Raya, A, Rodríguez-Pizà, I, Guenechea, G, Vassena, R, Navarro, S, Barrero, MJ et al.. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460: 53-59

Center for Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain.
Nature (Impact Factor: 41.46). 06/2009; 460(7251):53-9. DOI: 10.1038/nature08129
Source: PubMed


The generation of induced pluripotent stem (iPS) cells has enabled the derivation of patient-specific pluripotent cells and provided valuable experimental platforms to model human disease. Patient-specific iPS cells are also thought to hold great therapeutic potential, although direct evidence for this is still lacking. Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free. These data offer proof-of-concept that iPS cell technology can be used for the generation of disease-corrected, patient-specific cells with potential value for cell therapy applications.

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Available from: Antonella Consiglio, Oct 08, 2015
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    • "Multiple studies have proved the utility of this approach (reviewed in Hanna et al., 2010; Han et al., 2011; Bellin et al., 2012; Imaizumi and Okano, 2014). Moreover, recent studies showed that mutations in patient-derived iPSCs can be corrected by genomic manipulations (Raya et al., 2009; Zou et al., 2009; Howden et al., 2011). However, many ASD-and schizophrenia-associated mutations exhibit incomplete penetrance, suggesting that genetic background effects significantly influence the clinical presentation and could contribute to the observed phenotypes. "
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    ABSTRACT: Heterozygous mutations of the NRXN1 gene, which encodes the presynaptic cell-adhesion molecule neurexin-1, were repeatedly associated with autism and schizophrenia. However, diverse clinical presentations of NRXN1 mutations in patients raise the question of whether heterozygous NRXN1 mutations alone directly impair synaptic function. To address this question under conditions that precisely control for genetic background, we generated human ESCs with different heterozygous conditional NRXN1 mutations and analyzed two different types of isogenic control and NRXN1 mutant neurons derived from these ESCs. Both heterozygous NRXN1 mutations selectively impaired neurotransmitter release in human neurons without changing neuronal differentiation or synapse formation. Moreover, both NRXN1 mutations increased the levels of CASK, a critical synaptic scaffolding protein that binds to neurexin-1. Our results show that, unexpectedly, heterozygous inactivation of NRXN1 directly impairs synaptic function in human neurons, and they illustrate the value of this conditional deletion approach for studying the functional effects of disease-associated mutations. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Stem Cell 08/2015; 17(3). DOI:10.1016/j.stem.2015.07.017 · 22.27 Impact Factor
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    • "Because hiPSCs are developed from a patient’s own somatic cells, it is believed that hiPSCs-based therapy would be very poorly or non-immunogenic, whereas hESCs are not (125–128). The use of these cells provides an accessible, genetically tractable, and homogenous starting cell population to efficiently study human blood cell development among others (100, 103, 108, 111, 129). hESCs and hiPSCs can provide important starting cell populations to develop new cell-based therapies that have the potential to treat both malignant and non-malignant diseases. "
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    ABSTRACT: Natural killer (NK) cells play an essential role in the fight against tumor development. Over the last years, the progress made in the NK-cell biology field and in deciphering how NK-cell function is regulated, is driving efforts to utilize NK-cell-based immunotherapy as a promising approach for the treatment of malignant diseases. Therapies involving NK cells may be accomplished by activating and expanding endogenous NK cells by means of cytokine treatment or by transferring exogenous cells by adoptive cell therapy and/or by hematopoietic stem cell transplantation. NK cells that are suitable for adoptive cell therapy can be derived from different sources, including ex vivo expansion of autologous NK cells, unstimulated or expanded allogeneic NK cells from peripheral blood, derived from CD34+ hematopoietic progenitors from peripheral blood and umbilical cord blood, and NK-cell lines. Besides, genetically modified NK cells expressing chimeric antigen receptors or cytokines genes may also have a relevant future as therapeutic tools. Recently, it has been described the derivation of large numbers of functional and mature NK cells from pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, which adds another tool to the expanding NK-cell-based cancer immunotherapy arsenal.
    Frontiers in Immunology 09/2014; 5:439. DOI:10.3389/fimmu.2014.00439
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    • "Efficient generation of disease-free iPSCs from FA fibroblasts corrected by gene targeting To generate disease-free FA-iPSCs, FA fibroblasts subjected to gene editing (geFA-123, geFA-52 and geFA-52T) were first enriched for EGFP + cells by cell sorting and then reprogrammed using a polycistronic excisable LV expressing the human SOX2, OCT4, KLF4, and cMYC transgenes from the EF1A promoter (STEMCCA vector; Somers et al, 2010). Consistent with previous observations (Raya et al, 2009), uncorrected FA fibroblasts did not generate iPSCs after reprogramming, even after transduction with the TERT-LV (data not shown). Although several iPSC-like colonies were generated from gene-edited FA-123 fibroblasts (115 AP + cells/100,000 fibroblasts ), no stable iPSC lines could be generated from FA fibroblasts simply subjected to gene editing, most probably because of the pro-senescence nature of these cells. "
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    ABSTRACT: Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective lentiviral vectors to demonstrate for the first time that FANCA can be efficiently and specifically targeted into the AAVS1 safe harbor locus in fibroblasts from FA-A patients. Strikingly, up to 40% of FA fibroblasts showed gene targeting 42 days after gene editing. Given the low number of hematopoietic precursors in the bone marrow of FA patients, gene-edited FA fibroblasts were then reprogrammed and re-differentiated toward the hematopoietic lineage. Analyses of gene-edited FA-iPSCs confirmed the specific integration of FANCA in the AAVS1 locus in all tested clones. Moreover, the hematopoietic differentiation of these iPSCs efficiently generated disease-free hematopoietic progenitors. Taken together, our results demonstrate for the first time the feasibility of correcting the phenotype of a DNA repair deficiency syndrome using gene-targeting and cell reprogramming strategies.
    EMBO Molecular Medicine 05/2014; 6(6). DOI:10.15252/emmm.201303374 · 8.67 Impact Factor
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