Fanconi anemia (FA) is a complex genetic disorder characterized by congenital abnormalities, bone marrow failure, and my-eloid malignancies. Identification of 13 FA genes has been instrumental to explore gene transfer technologies aimed at correction of autologous FA-deficient stem cells. To date, 3 human FA stem cell gene therapy trials with standard 4-day trans-duction protocols using gammaretroviral vectors failed to provide clinical benefit. In addition, 2- to 4 day ex vivo manipulation of bone marrow from mice containing a disruption of the homologue of human FANCC (Fancc) results in a time-dependent increase in apoptosis and a risk for malignant transformation of hema-topoietic cells. Here, we show that a 14hour transduction period allows a foamy-viral vector construct expressing the human FANCC cDNA to efficiently transduce murine FA stem cells with 1 to 2 proviral integrations per genome. Functionally, the repopulating activity of Fancc -/- stem cells from reconstituted mice expressing the recombinant FANCC transgene was comparable with wild-type controls. Collectively, these data provide evidence that short-term transduction of c-kit+ cells with a foamyviral vector is sufficient for functional correction of a stem cell phenotype in a murine FA model. These data could have implications for future gene therapy trials for FA patients.
ASJC Scopus subject areas
- Cell Biology