title: Lentiviral-mediated genetic correction of hematopoietic and mesenchymal progenitor cells from Fanconi anemia patients.
abstract: Previous clinical trials based on the genetic correction of purified CD34(+) cells with gamma-retroviral vectors have demonstrated clinical efficacy in different monogenic diseases, including X-linked severe combined immunodeficiency, adenosine deaminase deficient severe combined immunodeficiency and chronic granulomatous disease. Similar protocols, however, failed to engraft Fanconi anemia (FA) patients with genetically corrected cells. In this study, we first aimed to correlate the hematological status of 27 FA patients with CD34(+) cell values determined in their bone marrow (BM). Strikingly, no correlation between these parameters was observed, although good correlations were obtained when numbers of colony-forming cells (CFCs) were considered. Based on these results, and because purified FA CD34(+) cells might have suboptimal repopulating properties, we investigated the possibility of genetically correcting unselected BM samples from FA patients. Our data show that the lentiviral transduction of unselected FA BM cells mediates an efficient phenotypic correction of hematopoietic progenitor cells and also of CD34(-) mesenchymal stromal cells (MSCs), with a reported role in hematopoietic engraftment. Our results suggest that gene therapy protocols appropriate for the treatment of different monogenic diseases may not be adequate for stem cell diseases like FA. We propose a new approach for the gene therapy of FA based on the rapid transduction of unselected hematopoietic grafts with lentiviral vectors (LVs).
authors.affiliation: División de Hematopoyesis y Terapia Génica, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, Madrid, Spain.
authors.forename: Ariana
authors.initials: A
authors.lastname: Jacome
authors.forename: Susana
authors.initials: S
authors.lastname: Navarro
authors.forename: Paula
authors.initials: P
authors.lastname: Río
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Yañez
authors.forename: Africa
authors.initials: A
authors.lastname: González-Murillo
authors.forename: M Luz
authors.initials: ML
authors.lastname: Lozano
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Lamana
authors.forename: Julian
authors.initials: J
authors.lastname: Sevilla
authors.forename: Teresa
authors.initials: T
authors.lastname: Olive
authors.forename: Cristina
authors.initials: C
authors.lastname: Diaz-Heredia
authors.forename: Isabel
authors.initials: I
authors.lastname: Badell
authors.forename: Jesus
authors.initials: J
authors.lastname: Estella
authors.forename: Luis
authors.initials: L
authors.lastname: Madero
authors.forename: Guillermo
authors.initials: G
authors.lastname: Guenechea
authors.forename: José
authors.initials: J
authors.lastname: Casado
authors.forename: Jose C
authors.initials: JC
authors.lastname: Segovia
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bueren
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D005199:Fanconi Anemia / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D005822:Genetic Vectors / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*
chemical_list: D018952:Antigens, CD34