Recombinant DNA Advisory Committee - 12/2-3/93 
Dr. Walters called on Dr. Parkman to present his primary review of the protocol 
submitted by Drs. Johnson M. Liu and Neal S. Young of NIH, Bethesda, Maryland. Dr. 
Parkman stated that Fanconi anemia is an autosomal recessive genetic disease in which 
the affected individuals have an inability to repair spontaneous or induced DNA breaks. 
As a consequence of their decreased capacity to repair DNA breaks, patients develop 
aplastic anemia, have an increased likelihood of cancer development, and may have 
anatomic abnormalities involving the skeleton and kidney. Four complementation 
groups of Fanconi anemia have been defined. The gene responsible for the defect, 
Fanconi anemia complementation C (FACC) has been identified and cloned. The 
protein product of FACC is 63 kd; however, the function of this protein is unknown. 
The investigators have demonstrated that in vitro transduction of the FACC gene into 
patients' cells (B lymphoblast cell lines and target CD34( + ) cells) results in the 
normalization of the sensitivity of the transduced cells to mitomycin C treatment and a 
reduction in the number of induced chromosomal breaks. The investigators have 
demonstrated in this preclinical model that transduction of abnormal cells with the 
FACC gene can result in the physiological normalization of these cells. The proposed 
study is similar to the Gaucher's disease protocols previously approved by the RAC in 
that CD34( + ) cells will be isolated from peripheral blood following granulocyte colony 
stimulating factor (G-CSF) stimulation. The use of peripheral blood cells eliminates the 
possible risk associated with the use of general anesthesia for bone marrow harvesting. 
Questions still exist about the relative quality and frequency of obtaining true pluripotent 
hematopoietic stem cells from peripheral blood versus bone marrow cells. Considering 
the risks of general anesthesia, the present approach is appropriate for the proposed 
study. CD34( + ) cells will be isolated using the CellPro® monoclonal antibody column 
and transduced in vitro with the retroviral vector in the presence of the growth factors, 
interleukin-3 (IL-3), interleukin-6 (IL-6), and G-CSF. The cells will be reinfused into 
patients following transduction. Patients will receive a maximum of 4 infusions over a 
period of 12 months, at a frequency of * every 2 months. Peripheral blood and bone 
marrow cells will be analyzed for the presence of the transduced FACC gene and its 
functional effect of conferring resistance to mitomycin C. This protocol is a logical 
extension of the investigators' previous work on Gaucher's disease and the Autologous 
Bone Marrow Transplant Program at NIH. If a significant in vivo selective growth 
advantage is demonstrated for the transduced stem cells and their progeny, this study 
may result in a potential clinical benefit. The investigators have adequately responded to 
most of the issues raised in the primary review. 
Review-Dr. Smith 
Dr. Smith stated that although the investigators partially responded to some of the 
questions posed in his written comments, there are several issues that require further 
discussion. One major concern is the use of growth factors both in patients and during 
the transduction procedure. CD34( + ) cells will be harvested following mobilization with 
G-CSF. In patients with non-Fanconi's myelodysplastic syndromes, growth-factor 
administration can result in elevated blast counts, presenting the theoretical risk of 
accelerating progression to acute leukemia. Similarly, ex vivo treatment of the harvested 
progenitor cells with a cocktail of experimental growth factors (IL-3, G-CSF, and IL-6) 
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Recombinant DNA Research, Volume 18 
