APPENDIX D. 
Non-Technical Abstract 
DESCRIPTION OF PROPOSED STUDY 
GENE THERAPY FOR RECURRENT PEDIATRIC BRAIN TUMORS 
In an attempt to improve the grim prognosis associated with malignant pediatric brain 
tumors, a novel therapeutic approach to these tumors is being investigated. This approach 
uses recombinant DNA technology to transfer a gene which confers sensitivity to an 
antiviral drug into the tumor. This is achieved by direct injection of the tumor with cells 
which actively produce a retroviral vector carrying the sensitivity gene. The agent of 
transfer, or vector, is a retrovirus which has been modified so that it cannot reproduce 
itself. Such vectors are capable of stably incorporating their genetic material into the DNA 
of the host. The producer cell is an NTH 3T3 (mouse fibroblast) cell that has been 
genetically engineered to continually produce retroviral vectors. The vectors are inserted 
into dividing cells. Since normal brain cells are not actively growing or dividing, insertion 
of the producer cells into a brain tumor will result in vectors entering only the proliferating 
tumor cells. The vectors incorporate their DNA into the tumor cells, including the drug 
sensitivity gene. The gene leads the tumor cells to express a protein (herpes simples virus 
enzyme thymidine kinase or HS-tk) that sensitizes the cells to an antiviral drug (ganciclovir 
or GCV). When GCV is administered systemically, cells expressing the HS-tk protein 
convert GCV into a toxic substance intracellularly that leads to the death of the affected 
cells. Normal human cells inside and outside the brain are not sensitive to GCV. The 
selective uptake of the vector, therefore, allows specific cell kill of the affected tumor cells 
while sparing the adjacent normal brain cells and the cells outside the brain. This type of 
gene transfer has several unique features. First, these retroviral vectors only integrate and 
express their genes in cells which are actively synthesizing DNA. The brain in unique 
because normal brain cells are not mitotically active in children beyond 2 years of age. 
Therefore, only the actively dividing tumor cells arc expected to express the HS-tk enzyme 
and become target for GCV; surrounding non-proliferating normal brain tissue should not 
acquire the HS-tk gene and will remain insensitive to GCV. Second, all of the transduced 
tumor cells (and retroviral vector producing cells) will be killed by the host immune 
response and/or GCV treatment, eliminating potential concern about vector- related changes 
giving rise to malignant cells in the tumor region or elsewhere. 
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