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

Jennifer E. Adair, Xin Zhao, Sylvia Chien, Min Fang, Martin E. Wohlfahrt, Grant D. Trobridge, Jason A. Taylor, Brian C. Beard, Hans Peter Kiem, Pamela S. Becker

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1283-1294
Number of pages12
JournalJournal of Molecular Medicine
Issue number11
StatePublished - Nov 2012
Externally publishedYes


  • Autologous transplantation
  • Cyclophosphamide
  • Fanconi anemia
  • Gene therapy
  • Lentivirus vector

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)


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