Recombinant DNA Advisory Committee- 9/12-13/94 
protocol will study the endpoints such as improvement of severe leg pain and healing of 
ulcers besides angiographic and physiologic measurements, and thus has some elements of 
a therapeutic protocol. Dr. Motulsky was concerned that mildly favorable effects on pain 
that patients notice in the study may be due to placebo effects. A control group of 
patients will be valuable although he recognized problems with this study design. Dr. 
Motulsky suggested that a small pilot study with about 2 to 4 patients will be useful if a 
control study is needed. Dr. Motulsky asked if there are extensive studies to examine for 
dissemination of the DNA from the artery into the blood stream and into other organs. 
Most of the people to be studied are old men with arteriosclerotic heart disease and many 
have diabetes. VEGF has a potential for contributing to diabetic retinopathy by 
stimulating new vessel growth. The Type I diabetic patients will be excluded but some 
Type II diabetics may be eligible since the risk posed by the protocol is low. The 
investigators provided satisfactory answers in writing that no plasmid DNA has been 
detected in brain, lung, heart, liver, and gonads in animal studies. Dr. Motulsky said that 
the statement regarding cost in the Informed Consent document should be clarified. Do 
the investigators imply that certain costs will be charged to the patients’ insurance even 
though many additional tests related to the gene therapy are required? Dr. Motulsky had 
reviewed Dr. Dzau’s comment, and Dr. Motulsky agreed with Dr. Parkman’s opinion that 
the investigators have addressed most of his concerns. In rejecting the idea of a control 
group in the study, the investigators responded in writing that the additional risk of 
catheter manipulation to the PAD patients is a factor for favoring the present study 
design. 
Dr. Parkman added that the investigators answered the question about the use of the 
recombinant VEGF protein. Gene transfer is preferred over bolus injection of 
recombinant VEGF protein for two reasons: (1) the recombinant product is not available 
for clinical trial at present and will be expensive, and (2) the local continuous production 
of VEGF following gene transfer is favored over systemic peptide administration, since the 
latter will peak and decline quickly. Dr. Parkman noted that gene therapy may be 
cheaper in this case. 
Review-Dr. Secundy 
Dr. Secundy said that she had only a minor comment on the statement about autopsy in 
the Informed Consent document. It should always be stated that autopsy will be 
requested not required. The investigators have responded to this concern. Dr. Secundy 
was very pleased to see a clear Informed Consent document, and the statement on patient 
charges is what the RAC recommended. She favored approval of the protocol. 
Other Comments 
Dr. Erickson said it is important to point out that this is the first time that gene therapy 
would be applied to patients in advance of other types of therapy, including recombinant 
growth factors. 
Dr. Straus would like the investigators to elaborate on the issue of retinopathy. He said 
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Recombinant DNA Research, Volume 20 
