Topics in Pediatric Leukemia -- Fanconi's Anemia: New Insights

Noah Federman, MD; Kathleen M. Sakamoto, MD, PhD

In This Article

Gene Therapy

Somatic mosaicism, which has been reported in FA patients, supports the modality of gene therapy as a therapeutic option. In FA mosaic patients, there is reversion of a pathogenic allele in a single hematopoietic progenitor cell to a wild-type one, thereby conferring a survival advantage to that cell. The patients with this mosaicism remain in remission from bone marrow failure.[24] This indicates that correction of a single progenitor cell may be all that is required to restore adequate hematopoiesis.

As mentioned before, phenotypic correction of hematopoietic progenitors has been achieved in FANCA knockout mice with retroviral vectors.[25] However, retroviral vectors in human patients have proven ineffective because FA human bone marrow cells grow poorly in vitro, are fragile, and are refractory to retroviral vector transduction.[26] Clinical trials with retroviral vectors in FA patients have been disappointing. Lentiviral vectors, on the other hand, are being used in animal models with some success. FANCA and FANCC knockout mice bone marrow cells have been transduced with lentiviruses, and the deriving hematopoietic cells have become resistant to DNA crosslinking agents.[27]

Lentiviral vector gene therapy, although still in a very experimental phase, carries some promise for patients, as it can transduce quiescent hematopoietic progenitors in the absence of cytokines or other growth factors.


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