Recombinant DNA Advisory Committee - 2/10-11/92 
"confidentiality." Dr. Nabel has addressed most of the serious concerns of the HGTS. Dr. 
R. Murray said that he would recommend approval of the protocol after Dr. Nabel 
addresses the issues raised by the reviewers. 
Review-Mr. Mannix 
Mr. Mannix described the protocol as involving in vivo modification of human cells. This 
protocol represented an incremental step in gene therapy with several reassuring features. 
The treatment is relatively safe based on the fact that the transfecting agent is not a virus 
but a DNA-containing liposome with no capacity to reproduce for prolonged survival in a 
potent form. The patients have a life expectancy of six months and no reproductive 
capacity. There is essentially no public health risk associated with this protocol. There 
are still some concerns regarding the therapeutic mechanism of this treatment. 
Presentation-Dr. Nabel 
Dr. Nabel responded to Dr. R. Murray's comment by confirming that the investigators will 
be using liposomal transfection rather than direct retrovirus infection. Dr. Nabel stated 
that it was his interest in transcription factors and how they regulate gene expression in 
vivo that led the investigators to attempt site-specific gene expression in vivo. Removing 
cells, transducing them in vitro , and reintroducing them into experimental animals cost the 
investigators time and the character of the cells was often changed, therefore, direct 
introduction of genes would be preferable. In subsequent studies, retroviral transduction 
was compared to direct DNA/liposome introduction into the aortic vessel walls using a 
catheter technique. This technique provided a quick, convenient method for achieving 
site-specific gene expression in vivo. By introducing this material under carefully 
controlled conditions and maintaining a transluminal pressure gradient across the vessel 
wall, the DNA could be introduced into the animal's artery. 
Dr. Nabel showed an in situ autoradiogram illustrating a DNA/liposome complex that was 
radiolabeled with S 35 demonstrating a gradient of radiolabeled DNA across the vessel wall. 
Gene expression was detected in all three layers of the vessel wall. He described 
experiments that demonstrated the induction of immune response as a result of the 
introduction of a foreign MHC gene, HLA-B7, into the arterial vessel wall in a pig animal 
model. The observed immune response was extremely potent as well as focal; therefore, 
creating an initial response to the foreign gene that stimulates local tissue damage and 
injury which in turn creates a localized processing and presentation of the foreign antigen 
that creates the inflammation seen in the vessel wall. In time, the inflammation 
completely dissipates. 
Dr. Nabel said that it was the profound inflammatory response seen in the pig model that 
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