Engraftment of hematopoietic progenitor cells transduced with the Fanconi anemia group C gene (FANCC)

Fanconi anemia (FA) is an autosomal recessive disorder that leads to aplast ic anemia. Mutations in the FANCC gene account for 10-15% of cases. FA cell s are abnormally sensitive to DNA-damaging agents such as mitomycin C (MMC) . Transfection of normal FANCC into mutant cells corrects this hypersensiti vity and improves their viability in vitro. Four FA patients, representing the three major FANCC mutation subgroups, were entered into a clinical tria l of gene transduction aimed at correction of the hematopoietic defect. Thr ee patients received three or four cycles of gene transfer, each consisting of one or two infusions of autologous hematopoietic progenitor cells that had been transduced ex vivo with a retroviral vector carrying the normal FA NCC gene. Prior to infusion, the FANCC transgene was demonstrated in transd uced CD34-enriched progenitor cells. After infusion, FANCC was also present transiently in peripheral blood (PB) and bone marrow (BM) cells. Function of the normal FANCC transgene was suggested by a marked increase in hematop oietic colonies measured by in vitro cultures, including colonies grown in the presence of MMC, after successive gene therapy cycles in all patients. Transient improvement in BM cellularity coincided with this expansion of he matopoietic progenitors. A fourth patient, who received a single infusion o f transduced CD34-enriched BM cells, was given radiation therapy for a conc urrent gynecologic malignancy. The FANCC transgene was detected in her PB a nd BM cells only after recovery from radiation-induced aplasia, suggesting that FANCC gene transduction confers a selective engraftment advantage. The se experiments highlight both the potential and difficulties in applying ge ne therapy to FA.