Recombinant DNA Advisoiy Committee - 12/2-3/93 
conversion from preleukemic to a leukemic state. Dr. Liu acknowledged that there is a 
theoretical concern about leukemic conversion which led the Pis to limit the 
administration of G-CSF to a 1 week period. Patients will be placed under close 
observation for this potential risk. Drs. Smith and Doi expressed concern that patients 
will be included who have clonal karyotypic abnormalities of their blood cells. Dr. Liu 
responded that retrospective studies of Fanconi anemia patients suggest that there is no 
association of clonal karyotypic abnormalities with the onset of leukemia. Fanconi 
anemia is a very rare genetic disease, which places severe limitations on the eligibility 
criteria. In response to Dr. Smith's question regarding the use of growth factors during 
the ex vivo transduction procedure, Dr. Liu stated that these procedures are designed to 
stimulate hematopoietic progenitor cells to divide in order to enhance transduction 
efficiency. There is very limited experience to indicate whether these factors are 
necessary for transduction of cells from Fanconi anemia patients. Dr. Smith was 
concerned that growth factors such as IL-6, IL-3, and G-CSF could result in the 
outgrowth of preleukemic cells during the transduction procedure. Dr. Liu explained 
that these growth factors have been used previously to treat patients who either are 
preleukemic or leukemic. There is no data indicating that these patients are at high risk 
of accelerating leukemia development. Dr. Post remarked that Dr. Cynthia Dunbar's 
semi-annual data report form (RAC protocol #9206-025) indicated that recent data 
suggests the possibility that G-CSF may favor the growth of leukemic versus normal 
progenitors during the ex vivo culture. Dr. Post agreed with Dr. Smith's concern about 
the use of growth factors during the transduction of cells from Fanconi anemia patients. 
Dr. Young, co-PI on the proposed study, responded that the in vitro data demonstrating 
leukemia cell proliferations by G-CSF or GM-CSF (granulocyte-macrophage colony 
stimulating factor) involved cells obtained from patients with acute or chronic 
myelogenous leukemia. This proposal involves Fanconi anemia patients, not 
myelogenous leukemia patients. Dr. Young stated that it is unreasonable to exclude the 
use of growth factors based on in vitro observations. Dr. Smith suggested that the 
investigators should contact Dr. Dunbar and request additional data regarding her 
observations. 
In response to Dr. Post's question about murine transplantation experiments, Dr. Liu 
stated that these studies are ongoing. Bone marrow was obtained from C57/B16 mice 
and transduced with the FACC vector. These transduced cells were then reinfused into 
recipient W/W v mice. Preliminary data indicate successful engraftment and transduction 
of the FACC gene into the stem cells of recipient mice. No abnormalities have been 
observed by necropsy of one recipient. Data are currently unavailable with regard to in 
vivo expression or transduction efficiency of the FACC gene. Ms. Grossman expressed 
her reservations about the lack of data derived from a relevant animal model. Dr. 
Miller remarked that the murine model will be useful to address many of the safety 
issues that have been posed by the RAC. If the transduced FACC gene is adequately 
expressed in mice, concerns about untoward effects of the FACC gene on normal cells 
can be addressed. Dr. Liu said that the suggested in vivo studies are in progress. 
Committee Motion #1 
[526] 
Recombinant DNA Research, Volume 18 
