Recombinant DNA Advisory Committee - 03/1-2/93 
Dr. Straus stated that the investigators need to expand on the status of the baboon 
studies. Is it true that human adenoviruses do not replicate in baboon cells? Is the 
baboon a relevant animal model? Will individuals be excluded from participation in the 
study if they demonstrate expression of El gene products. This stipulation was part of 
the exclusion criteria for Dr. Crystal's protocol. El has been shown to complement 
adenoviruses. Dr. Parkman explained that during the course of reviewing Dr. Crystal's 
protocol. Dr. Harold Ginsberg (an ad hoc consultant during the December 1992 
meeting) stated that complementation by El should not present any deleterious effects; 
therefore, this exclusion criterion is unnecessary. 
Presentation~Dr. Boucher 
Dr. Boucher explained that the nasal epithelium was chosen as the target for this Phase I 
study because it provides a defined region that can be easily assessed in opder to obtain 
electrochemical measurements and biopsy samples. Valuable information will be 
obtained about the safety and efficacy of the gene transfer procedure. The respiratory 
epithelium of the nasal cavity is very similar to the airways; therefore, it is a very 
pertinent model. 
i 
He presented data demonstrating the fraction of cells in the epithelial sheet that have to 
be corrected in order to restore the ion transport defect that characterizes CF. Using an 
artificial system of immortalized epithelial cells, gene transduction correct the 
electrophysiological defect in approximately 10% of the epithelial sheet. This system is 
artificial, and it is unclear that the same results will be observed in vivo. A transduction 
rate higher than 10% will probably have to be achieved in humans to see any significant 
correction in the electrophysiological defect. 
I 
He presented in vitro data demonstrating that approximately 1 x 10 10 pfu are required to 
obtain maximum gene transfer in both nasal and bronchial epithelial cells. Therefore, 
the nasal cavity should represent a good model in which to study the efficacy of gene 
transfer in the lower airways. Experiments were presented demonstrating that the vector 
is capable of correcting the chloride transport defect in primary cultures of cells obtained 
from CF patients. 
Using a murine model, the investigators have been able to demonstrate that the in vitro 
dose-response observation correlates with the in vivo response. Both human and murine 
nasal epithelial cells are transduced at the same rate whli the proposed vector. 
Therefore, the mouse is an appropriate in vivo model for efficacy studies. The in vivo 
murine model was characterized. A cylinder is inserted into the trachea which allows for 
the administration of a known concentration and volume of virus. This area can be 
isolated for a defined period of time and provides the opportunity to determine the 
efficacy of gene transfer in a defined surface area. Exposure to 1 x 10 11 pfu per ml for 
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Recombinant DNA Research, Volume 17 
