title: In vivo proliferation advantage of genetically corrected hematopoietic stem cells in a mouse model of Fanconi anemia FA-D1.
abstract: Fanconi anemia (FA) is an inherited recessive DNA repair disorder mainly characterized by bone marrow failure and cancer predisposition. Studies in mosaic FA patients have shown that reversion of one inherited germ-line mutation resulting in a functional allele in one or a few hematopoietic stem cells (HSCs) can lead to the proliferation advantage of corrected cells, thus over time normalizing the hematologic status of the patient. In contrast to these observations, it is still unclear whether ex vivo genetic correction of FA HSCs also provides a similar proliferation advantage to FA HSCs. Using an FA mouse model with a marked hematopoietic phenotype, the FA-D1 (Brca2(Delta27/Delta27)) mice, we demonstrate that the lentivirus-mediated gene therapy of FA HSCs results in the progressive expansion of genetically corrected clones in mild-conditioned FA-D1 recipients. Consistent with these data, hematopoietic progenitors from FA recipients progressively became mitomycin C resistant and their chromosomal instability was reverted. No evidence of myelodysplasia, leukemias, or abnormal clonal repopulation was observed at multiple time points in primary or secondary recipients. Our results demonstrate that ectopic expression of BRCA2 confers a beneficial in vivo proliferation advantage to FA-D1 HSCs that enables the full hematopoietic repopulation of FA recipients with genetically corrected cells.
authors.affiliation: Hematopoiesis and Gene Therapy Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas and Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Río
authors.forename: Néstor W
authors.initials: NW
authors.lastname: Meza
authors.forename: Africa
authors.initials: A
authors.lastname: González-Murillo
authors.forename: Susana
authors.initials: S
authors.lastname: Navarro
authors.forename: Lara
authors.initials: L
authors.lastname: Alvarez
authors.forename: Jordi
authors.initials: J
authors.lastname: Surrallés
authors.forename: Maria
authors.initials: M
authors.lastname: Castella
authors.forename: Guillermo
authors.initials: G
authors.lastname: Guenechea
authors.forename: José C
authors.initials: JC
authors.lastname: Segovia
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.forename: Juan A
authors.initials: JA
authors.lastname: Bueren
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005199:Fanconi Anemia / Q000473:pathology* / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D018095:Germ-Line Mutation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice
chemical_list: D024682:BRCA2 Protein