Recombinant DNA Advisory Committee - 12/2-3/93 
carries a similar risk of increasing the susceptibility of an abnormal stem cell becoming 
leukemic or furthering the growth potential of an already extant leukemic cell clone. 
This theoretical risk is not adequately described in the protocol. The investigators have 
not stated clearly that the proposed treatment only attempts to correct the hematopoietic 
cells, not other cells that are affected by this disease. The investigators have only 
provided short-term tissue culture data. Dr. Smith posed the following questions. What 
are the long-term effects of inserting the FACC gene under constitutive expression 
conditions that alter normal cellular function? Will the transduced cells be selected in 
G418? Can adequate numbers of CD34( + ) cells be harvested from these aplastic 
patients? There is little information available about how the gene defect actually results 
in disease. Fanconi anemia is an appropriate candidate for gene transfer experiments 
and the investigators are well qualified to conduct such experiments; however, these 
issues must be addressed before the RAC makes a recommendation regarding approval. 
Review-Dr. Carmen 
Dr. Carmen stated that since the RAC has never reviewed any human gene transfer 
proposal for the treatment of the genetic disease Fanconi anemia, the RAC should 
provide a careful review of this novel approach. The investigators have not provided 
data in an appropriate animal model, citing the fact that the exact biochemical function 
of the FACC gene is unknown. The protocol currently states that the Pis are "currently 
investigating the effect of long-term expression of the gene in a murine transplantation 
model." Ordinarily, recommending approval of a protocol that does not include a 
preclinical animal model is unusual, especially since patients will be £ 18 years of age. 
However, the investigators have provided adequate human ex vivo data to support the 
proposed study. Lymphoblast cell lines and CD34(+) cells isolated from Fanconi 
anemia patients were restored to their normal sensitivity to mitomycin C treatment 
following transduction with the FACC retroviral vector. He recommended modifications 
to the Informed Consent document that would make the language more understandable 
to laypersons and recommended approval of the protocol contingent on the acceptance 
of the modified Informed Consent document language. 
Other Comments 
Dr. Post expressed concern about the possible overproduction of the FACC protein, 
which has an unknown function in hematopoietic cells. He asked the investigators to 
provide additional information about the murine transplantation experiment that was 
conducted to determine the constitutive expression of the FACC gene. 
Investigator Response-Dr. Liu 
In response to Dr. Smith's concern about the use of growth factors in Fanconi anemia 
patients, Dr. Liu said that G-CSF has been used previously to treat several Fanconi 
anemia patients with severe pancytopenia for up to 1 year. One patient demonstrated a 
spontaneous clonal karyotypic abnormality prior to G-CSF treatment. To date, there is 
no evidence that treatment of Fanconi anemia patients with G-CSF poses the risk of 
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