Targeted gene therapy and cell reprogramming in Fanconi anemia

Paula Rio, Rocio Baños, Angelo Lombardo, Oscar Quintana-Bustamante, Lara Alvarez, Zita Garate, Pietro Genovese, Elena Almarza, Antonio Valeri, Begoña Díez, Susana Navarro, Yaima Torres, Juan P. Trujillo, Rodolfo Murillas, Jose C. Segovia, Enrique Samper, Jordi Surralles, Philip D. Gregory, Michael C. Holmes, Luigi NaldiniJuan A. Bueren

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59 Citations (Scopus)


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. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.
Original languageEnglish
Pages (from-to)835-848
JournalEMBO Molecular Medicine
Publication statusPublished - 1 Jan 2014


  • Cell reprogramming
  • Fanconi anemia
  • Gene-targeting
  • IPSCs
  • Zinc finger nucleases


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