Recombinant DNA Advisory Committee - 06/7-8/93 
The motion passed by a vote of 11 in favor, 5 opposed, and 3 
abstentions. 
ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE THERAPY PROTOCOL ENTITLED: GENE THERAPY FOR HUMAN BRAIN 
TUMORS USING EPISOME-BASED ANTISENSE cDNA TRANSCRIPTION OF 
INSULIN-LIKE GROWTH FACTOR /DR. I LAN 
Review--Dr. Miller 
Dr. Walters called on Dr. Miller to present his primary review of the protocol submitted 
by Dr. Joseph Ilan of Case Western Reserve University School of Medicine and 
University Hospitals of Cleveland, Cleveland, Ohio. Dr. Miller explained that an 
Epstein-Barr virus (EBV) vector will be used that directs the synthesis of antisense 
insulin growth factor (IGF)-l RNA and inhibits IGF-1 synthesis in glioblastoma cells 
obtained from patients with incurable brain tumors. Modified cells will be lethally 
irradiated and injected subcutaneously to stimulate immune destruction of tumor at 
peripheral sites. In vivo studies in rats support the feasibility of this technique. An 
episomal plasmid-based vector, which encodes EBV nuclear antigen- 1 and antisense 
IGF-1, will be introduced into tumor cells by liposome transfection. The cells will be 
lethally irradiated prior to injection; therefore, there are no vector-related safety issues. 
The animal data supports the potential clinical utility of this approach. He asked if the 
investigators have additional data demonstrating the transduction of the antisense 
construct and inhibition of IGF-1 in human cells. Antisense IGF-1 expression is driven 
by a metallothionein promoter, which is inducible by metal ions. He asked whether the 
level of metal ions in the patients' body is sufficient to induce the promoter to express 
antisense RNA. Dr. Miller recommended that the protocol should be approved. 
Review-Dr. Geiduschek 
Dr. Geiduschek explained that the episomal vector used in this study is a circular piece 
of DNA that replicates within the cell nucleus; therefore, it is not an integral component 
of the chromosomes. Dr. Miller added that the reason for using an episomal vector for 
antisense expression is that it will replicate to high copy number when transfected into 
target cells and will produce high levels of antisense RNA necessary to inhibit IGF-1 
production. 
Dr. Geiduschek said that this protocol proposes a potential therapy of an otherwise 
incurable disease in a conceptually coherent and generally persuasive way. The majority 
of his initial concerns have been responded to with the following exceptions: (1) Does 
the PI have experience generating the required quantities of cells from surgically 
acquired specimens? and (2) Does the PI have experience in producing large quantities 
Recombinant DNA Research, Volume 17 
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