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J Mol Med (Berl). 2012 Nov;90(11):1283-94. doi: 10.1007/s00109-012-0905-0. Epub 2012 Jun 3.

Cyclophosphamide promotes engraftment of gene-modified cells in a mouse model of Fanconi anemia without causing cytogenetic abnormalities.

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Division of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA.


A major hurdle for hematopoietic stem cell (HSC) gene therapy for inherited bone marrow disorders, including Fanconi anemia (FA), is adequate engraftment of gene-modified cells. A phenotypic defect in DNA repair renders FA patients sensitive to alkylating agents such as cyclophosphamide (Cy); however, at lower doses, Cy is well tolerated in the FA transplant setting. We tested whether non-alkylating agents could replace Cy for pretransplant conditioning to enhance engraftment of FANCA gene-modified hematopoietic cells. We compared Cy preconditioning with fludarabine (Flu) or cytarabine (AraC) or no conditioning as a control in fanca ( -/- ) mutant mice receiving gene-modified bone marrow cells. Only mice conditioned with Cy exhibited appreciable engraftment of gene-modified cells by PCR and resistance to mitomycin C (MMC). Cy administration following transplantation increased gene marking levels in all animals treated, but highest gene marking and corresponding MMC resistance were observed in mice receiving Cy pre- and posttransplantation. Importantly, no cytogenetic abnormalities were observed in Cy-treated mice. We conclude that Cy is an effective and superior preparative regimen with respect to engraftment of lentivirus-transduced cells and functional correction in fanca ( -/- ) mice. Thus, appropriately dosed Cy may provide a suitable conditioning regimen for FA patients undergoing HSC gene therapy.

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