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Pàgina inicial > Articles > Articles publicats > Targeted gene therapy and cell reprogramming in Fanconi anemia |
Data: | 2014 |
Resum: | 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. |
Ajuts: | European Commission 222878 European Commission 305421 European Commission 249845 Ministerio de Economía y Competitividad PLE 2009/0100 Ministerio de Economía y Competitividad SAF 2009-07164 Ministerio de Economía y Competitividad SAF 2012-39834 Ministerio de Ciencia e Innovación SAF2012-31881/ Instituto de Salud Carlos III RD06/0010/0015 Instituto de Salud Carlos III RD12/0019/0023 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-0489 |
Nota: | Altres ajuts: European Regional Development FEDER Funds, Italian Ministry of Health, Fondo de Investigaciones Sanitarias, Dirección General de Investigación de la Comunidad de Madrid S2010/BMD-2420, La Fundació Privada La Marató de TV3 121430/31/32, Marató de TV3 464/C/2012 |
Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Matèria: | Cell reprogramming ; Fanconi anemia ; Gene-targeting ; Ipscs ; Zinc finger nucleases |
Publicat a: | EMBO molecular medicine, Vol. 6, Issue 6 (June 2014) , p. 835-848, ISSN 1757-4676 |
15 p, 1.3 MB |