Preclinical protocol for in vivo selection of hematopoietic stem cells corrected by gene therapy in fanconi anemia group C

Meenakshi Noll, Raynard L. Bateman, Alan D. D'Andrea, Markus Grompe

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35 Scopus citations


Fanconi anemia (FA) is an autosomal recessive disorder characterized by birth defects, increased incidence of malignancy, progressive bone marrow failure, and cellular hypersensitivity to DNA cross-linking agents. Bone marrow transplantation is therapeutic and therefore FA is a candidate disease for hematopoietic gene therapy. We have previously used mitomycin C (MMC) to achieve in vivo selection of wild-type hematopoietic stem cells (HSC) transplanted into FANCC knockout mice. However, clinical application of MMC in human FA gene therapy is unlikely because of its unknown toxicity profile in human FA patients. In contrast, cyclophosphamide (CPA) and γ-irradiation (IR) are already in use with human FA patients and we therefore tested these regimens for their ability to achieve selection of genetically corrected HSCs in vivo. We found that nonmyeloablative doses of CPA or IR or combinations of CPA + IR were highly efficient at achieving in vivo selection of transplanted wild-type HSC. Furthermore, this nontoxic regimen also selected FANCC-mutant HSC corrected by ex vivo retroviral gene therapy. We suggest those nontoxic doses of CPA and/or IR could also be used to enhance gene therapy in human FA patients.

Original languageEnglish (US)
Pages (from-to)14-23
Number of pages10
JournalMolecular Therapy
Issue number1
StatePublished - Jan 1 2001



  • Cyclophosphamide
  • Fanconi anemia
  • Gene therapy
  • Hematopoietic cells
  • Retroviral vector
  • γ-irradiation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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