Recombinant DNA Advisory Committee - 12/2-3/93 
for a uniformly fatal disease. CSF circulates around the brain and spinal cord and comes 
in contact with every cell of the leptomeninges. Injection of VPC into this space will 
yield important information about the pharmacodynamics of GCV and distribution of the 
VPC and vector. Such data will be valuable for future gene therapy applications. 
Dr. Haselkorn asked if tumor markers exist that would allow the investigators to 
distinguish between responding and non-responding tumors. Dr. Ram answered that 
although a few markers exist for glioblastoma, there are no known markers for 
leptomeningeal carcinomatosis. Dr. Doi asked if experiments had been performed to 
look for the presence of the HSV-tk gene in those patients who exhibited rapidly growing 
tumors. Dr. Ram responded that the biology of the tumor often changes after several 
resections. Dr. Miller stated that evidence of antitumor response justifies the expansion 
of this treatment to other diseases. 
To follow up on Dr. Doi's question, Ms. Grossman questioned whether the HSV-tk gene 
sequences were detected in the non-responding tumor group. Dr. Ram answered that in 
situ hybridization assays were performed only on resected tumor specimens obtained 
from the surgically accessible group. Such analysis may be inconclusive since the 
specimens were obtained 7 days after GCV treatment which eliminates the HSV-tk 
transduced cells. 
Dr. Parkman asked how the dynamics and distribution of VPC will be assessed. Will 
tumors block the ventricular system and the subarachnoid space? Dr. Ram replied that 
one of the exclusion criterion of the proposed study is evidence of such a blockage. CSF 
samples will be obtained from the ventricular system and from the lumbar spinal cord to 
monitor the dynamics and distribution of the vector and VPC. Dr. Ram noted that in 
vivo monkey experiments demonstrated even distribution of the vector and VPC between 
the cervical and lumbar spinal cord. 
Dr. Miller asked why post-mortem studies were not performed on most of the 
glioblastoma patients. Dr. Ram explained that it is often difficult to obtain permission 
from relatives, etc., to obtain post-mortem brain tissue. Dr. Leventhal acknowledged 
that such permission is often difficult to obtain. 
Committee Motion 
A motion was made by Dr. Smith and seconded by Dr. Secundy to approve the protocol. 
The motion passed by a vote of 13 in favor, 1 opposed, and 1 abstention. 
VII. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE TRANSFER PROTOCOL ENTITLED: RETROVIRAL MEDIATED GENE 
TRANSFER OF THE FANCONI ANEMIA COMPLEMENTATION GROUP C GENE 
TO HEMATOPOIETIC PROGENITORS OF GROUP C PATIENTS /DRS. LIU AND 
YOUNG 
Review~Dr. Parkman 
Recombinant DNA Research, Volume 18 
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