Recombinant DMA Advisory Committee - 6/9-10/94 
Review-Dr. Parkman 
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. This 
protocol is a resubmission of the proposal that was deferred by the RAC at its December 
2-3, 1993, meeting. The RAC deferred the protocol until the investigators returned to 
the full RAC with the following: (1) murine data demonstrating in vivo expression of the 
Fanconi anemia complementation group C (FACC) gene and safety data accumulated 
over a period of ^ 4 months demonstrating that the FACC-transduced cells do not result 
in any untoward effects; (2) data as cited in Dr. Cynthia Dunbar's semi-annual data 
report (Protocol #9206-025) regarding the possibility that "stem cell factor could favor 
the growth of leukemic versus normal progenitors during ex vivo culture periods"; and (3) 
revision to both the protocol and Informed Consent document to modify the eligibility 
criteria regarding the necessity for bone marrow examination following each reinfusion. 
Dr. Parkman said that this protocol is a meritorious study. Preclinical studies 
demonstrate that in vitro transduction of the FACC gene into lymphoblast cells of 
Fanconi anemia patients results in the normalization of sensitivity to mitomycin C 
treatment and a reduction in the number of induced chromosomal breaks. Two 
outstanding questions remained following the previous RAC review: (1) What are the 
long-term effects (^6 months) of the FACC transduced gene in murine bone marrow 
cells? and (2) Does the presence of granulocyte colony stimulating factor (G-CSF) during 
the transduction procedure promote the outgrowth of preleukemic cells? Dr. Cynthia 
Dunbar (Protocol #9206-025) previously reported that G-CSF provided a growth 
advantage to chronic myelogenous leukemia (CML) cells. In response to these 
questions, the investigators concluded: (1) published literature demonstrates that the 
administration of G-CSF to Fanconi anemia patients does not increase the probability of 
developing myeloid malignancy. (2) Data published by Dr. Cynthia Dunbar indicates 
that although the presence of the transmembrane form of the stem cell growth factor 
promotes a selective growth advantage to CML cells, the soluble form of this factor has 
no deleterious effect. The proposed transduction procedure includes the soluble form of 
the stem cell growth factor rather than the transmembrane form; therefore, selective 
growth advantage is not a safety concern. The investigators have provided long-term 
toxicology data derived from murine experiments demonstrating that no 
lymphoproliferative abnormality has been observed for a period of 6 months. Dr. 
Parkman stated that the RAC's previous concerns have been satisfactorily answered by 
the investigators; therefore, approval of the protocol is recommended. 
Review-Dr. Smith 
Dr. Smith agreed that most of the RAC's concerns have been addressed by the 
investigators. The question of stem cell factor in the transduction procedure has been 
addressed. The data demonstrated that this factor's effect is specific to CML cells 
whereas normal progenitors are not as sensitive. Although one may disagree as to the 
relative merits of various components of the growth factor cocktail to be used in the 
transduction procedure, the investigators have now provided sufficient reassurance to 
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