Recombinant DNA Advisory Committee - 12/1-2/94 
only in cases of imminent life-threatening disease from birth through the first few years of life, e.g, Tay-Sachs 
and alpha-thalassemia. One of the major difficulties that will be encountered is gene delivery to the fetus. It 
probably will be impossible to target the gene in a fetus younger than 4 months. In order to be effective, the 
gene would have to be delivered between 4 months and birth. 
Dr. Motulsky stated that both a fetal advocate and a maternal advocate would be required. The most 
appropriate choice for a fetal advocate would be a geneticist with expertise in the target disease. The most 
problematic issues will be: (1) the most appropriate time for gene delivery, and (2) the most appropriate 
candidates to receive this therapy. Should this therapy be made available only to those mothers who refuse 
abortion so that the fetus will be provided the best available treatment options? Should the therapy only be 
made available as an alternative option to mothers who have elected to have an abortion? There are 
convincing arguments for and against both options. 
Dr. Glorioso noted that animal experiments have shown that retrovirus gene delivery results in the correction 
of stem cell defects in fetal lung cells which results in long-term transgene expression after birth. In situations 
where immune rejection of transduced cells is a problem for gene therapy, in utero gene transfer could prove 
beneficial in cases were immune rejection is problematic. 
Mr. Capron stated that fetal gene therapy is a very pertinent issue for the RAC to address and suggested that 
experts in the field should be invited to educate the RAC on relevant issues. Mr. Capron disagreed with Dr. 
Motulsky regarding the necessity for a fetal advocate. Given the current legal and moral system, the pregnant 
woman should be provided with state-of-the-art information so that she and her mate (if involved in the 
decision making process) can make an informed decision. Mr. Capron said that it is inappropriate to have an 
individual who possesses authority to argue the case of the fetus as opposed to the mother’s choice. There are 
people who will disagree with this point of view, which is the reason that further public discussion is necessary. 
Dr. Walters stated that this discussion will be continued following Dr. Amy Patterson’s in utero gene therapy 
presentation. 
VIII. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN GENE TRANSFER 
PROTOCOL ENTITLED: INTRATUMORAL INJECTION OF HERPES SIMPLEX THYMIDINE KINASE 
VECTOR PRODUCER CELLS (PA317/GlTklSvNa.7) AND INTRAVENOUS GANCICLOVIR FOR THE 
TREATMENT OF LOCALLY RECURRENT OR PERSISTENT HEAD AND NECK CANCER /DR. 
GLUCKMAN 
Review-Dr. Parkman 
Dr. Walters called on Dr. Parkman to present his primary review of the protocol submitted by Dr. Jack 
Gluckman of the University of Cincinnati Medical Center, Cincinnati, Ohio. Dr. Parkman stated that this 
protocol is similar to other GTI sponsored protocols involving the injection of murine VPC secreting the HSV- 
TK vector followed by the intravenous administration of GCV. Preclinical studies have demonstrated that 
intratumoral injection of HSV-TK VPC (intracranial tumors) followed by GCV administration resulted in the 
tumor regression whereas no effect was observed on control tumors injected with VPC expressing LacZ. 
Dr. Parkman explained that this Phase I/H proposal involves the administration of HSV-TK VPC for 
persistent or recurrent head and neck tumors. Fourteen days following VPC injection, subjects will receive 5 
mg/kg GCV twice daily for 7 days. Subjects will be reevaluated on Day 30. Subjects who have evidence of 
antitumor response or stable disease will be eligible for 2 additional cycles of VPC/GCV therapy. Subjects 
must be greater than 18 years of age, have recurrent or persistent disease not amenable to curative therapy, 
not have received alternative therapy within 30 days prior to the initiation of this study or evidence of disease 
progression, and their tumors must be accessible to direct injection. 
Dr. Parkman raised several specific questions regarding the present protocol, some of which have been 
addressed by the investigators in their written response. The major principle used for cytokine evaluation in 
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