Recombinant DNA Advisory Committee- 9/12-13/94 
and requirement for completion of a medication diary 1 month prior to entry onto the 
study. 
Summary 
Drs. Jeffrey M. Isner and Kenneth Walsh of St. Elizabeth’s Medical Center, Tufts 
University, Boston, Massachusetts, may conduct gene transfer experiments on 12 subjects 
(>40 years of age) with PAD. A plasmid DNA vector, phVEGF165, encoding the human 
gene for VEGF will be used to express VEGF to induce collateral neovascularization. 
Percutaneous arterial gene transfer will be achieved using an angioplasty catheter with a 
hydrogel coated balloon to deliver the plasmid DNA vector to the artery. The objectives 
of the study are: (1) to determine the efficacy of arterial gene therapy to relieve rest pain 
and/or heal ischemic ulcers of the lower extremities in patients with PAD; (2) to 
document the safety of the phVEGF arterial gene therapy for therapeutic angiogenesis. 
The secondary objective is to determine the anatomic and physiologic extent of collateral 
artery development in patients receiving phVEGF arterial gene therapy. 
XVIII. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE TRANSFER PROTOCOL ENTITLED: TREATMENT OF ADVANCED CNS 
MALIGNANCY WITH THE RECOMBINANT ADENOVIRUS H5.020RSVTK : A PHASE I 
TRIAL /DRS. ECK AND ALAVI 
Review-Dr. Parkman 
Dr. Walters called on Dr. Parkman to present his primary review of the protocol 
submitted by Drs. Stephen L. Eck and Jane B. Alavi of the University of Pennsylvania 
Medical Center, Philadelphia, Pennsylvania, Dr. Parkman said that this is a "recombinant" 
protocol in which two elements of previously approved protocols have been combined to 
produce this new protocol. The backbone of the adenovirus vector used by the 
investigators at the University of Pennsylvania to transduce the human CFTR gene for the 
treatment of CF has been employed in this protocol to transduce the Herpes simplex virus 
thymidine kinase (HSV-TK) gene to treat brain tumors. The approach is similar to Dr. 
Oldfield’s study (Protocol #9206-019) to treat brain tumors using intra-tumoral 
transduction with the HSV-TK gene and intravenous GCV. The basis for this concept is 
that the introduction of the HSV-TK gene into brain tumor cells followed by the systemic 
administration of GCV will result in the local production of toxic metabolites of GCV that 
will cause the destruction of the transduced tumor cells as well as the destruction of the 
non-transduced tumor cells, due to a bystander effect. The mechanism of the bystander 
effect appears to be the transport of the GCV metabolites through intercellular channels, 
resulting in the destruction of tumor cells that have not been transduced. The innovative 
part of this protocol is the use of adenovirus rather than a retrovirus based vector. 
Retroviruses require cellular replication for effective transduction while the adenoviruses 
may be able to transduce cells without cell division. Therefore, it is possible that a higher 
proportion of the brain tumor cells maybe transduced although it is possible that some 
normal neurons may be transduced. The risk is similar to neurosurgery where removal of 
a brain tumor may result in removal of some normal tissue. If both therapies are shown 
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Recombinant DNA Research, Volume 20 
