ABSTRACT 
Scientific Abstra 
Fanconi anemia (FA) is a rare genetic disorder characterized by 
progressive pancytopenia, congenital abnormalities, and a 
predisposition to malignancy. Therapy is currently limited to 
allogeneic marrow transplantation; patients lacking a suitable 
donor usually die from aplasia or acute leukemia. Recently, 
mutation in a novel gene named FACC (Fanconi anemia C- 
complementing) has been identified as causing one type of FA. 
FACC mutations, which introduce splicing errors or stop codons, 
have been identified in ~15% of FA patients. We have recently 
been successful in functional complementation of four FA cell 
lines using retroviral vectors to transfer a copy of the normal 
FACC gene. We also analyzed the ability of our viral vectors to 
functionally correct hematopoietic progenitor cells from a 
patient bearing a splice donor mutation. As for the lymphoid 
cell lines, these CD34- enriched cells were extremely sensitive to 
MMC. After infection of these progenitor cells with viral 
vectors bearing normal FACC, the progenitors gave rise to 
increased numbers of colonies both in the absence and presence of 
up to 5 nM MMC, whereas control cells were completely destroyed 
by 1 nM MMC. In summary, we have demonstrated that: (1) 
retroviral vectors can be engineered to transfer a normal FACC 
gene to FA(C) lymphoid cell lines and primary hematopoietic 
cells; (2) introduction of a normal FACC gene into CD34+ 
progenitors markedly enhances their growth in the absence and 
presence of MMC. 
This study is designed to determine whether hematopoietic 
progenitors transduced with the normal FACC gene can be reinfused 
safely into FA(C) patients. CD34+ cells obtained from G-CSF 
mobilized peripheral blood will be transduced ex vivo over a. 72- 
hour period in the presence of IL-3, IL-6, and Stem Cell Factor 
with the FACC retroviral vector. These transduced cells will be 
reinfused into FA(C) patients. Patients will be monitored for 
toxicities as well as evidence of successful gene transfer and 
expression. The procedure will be repeated up to a total of 4 
times with each treatment 2-4 months apart. Theoretically, these 
rescued stem cells should have a selective growth advantage 
within the hypoplastic FA marrow environment in vivo. 
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Recombinant DNA Research, Volume 19 
