FUNCTIONAL CORRECTION OF FANCONI-ANEMIA GROUP-A HEMATOPOIETIC-CELLS BY RETROVIRAL GENE-TRANSFER

Fanconi anemia (FA) is an autosomal recessive genetic disorder charact erized by a variety of physical anomalies, hone marrow failure, and an increased risk for malignancy, FA cells exhibit chromosomal instabili ty and are hypersensitive to DNA cross-linking agents such as mitomyci n C (MMC). FA is a clinically heterogeneous disorder and can be functi onally divided into at least five different complementation groups (A- E), We previously described the use of a retroviral vector expressing the FAC cDNA in the complementation of mutant hematopoietic cells from FA-C patients. This vector is currently being tested in a clinical tr ial of ex vivo hematopoietic progenitor cell transduction. The FA-A gr oup accounts for over 65% of all FA cases, and the FAA cDNA was recent ly identified by both expression and positional cloning techniques. We report here the transduction and phenotypic correction of lymphoblast oid cell lines from four unrelated FA-A patients, using two amphotropi c FAA retroviral vectors. Expression of the FAA transgene was adequate to normalize cell growth, cell-cycle kinetics, and chromosomal breaka ge in the presence of MMC. We then analyzed the effect of retroviral v ector transduction an hematopoietic progenitor cell growth. After FAA transduction of mutant progenitor cells, either colony number or colon y size increased in the presence of MMC. In addition, FAA but not FAC retroviral transduction markedly improved colony growth of progenitor cells derived from an unclassified FA patient. FAA retroviral vectors should be useful for both complementation studies and clinical trials of gene transduction. (C) 1997 by The American Society of Hematology.