safer than direct administration to small airways. 
(2) Administer the vector to only one side of the nose and lung. While 
there undoubtedly will be some dispersion of the vector to the other 
side, there will be a significant concentration gradient that will 
permit comparison to the untreated side. Importantly, administration 
to only one side gives an additional measure of safety, particularly 
in the lung. Further, if administration to large bronchi does yield 
evidence of clinical efficacy, there is the chance of significant 
clinical improvement, since unilateral lung transplantation of 
individuals with CF yields marked clinical improvement. 
(3) Separate the protocol into three consecutive periods: baseline, 
vehicle control, and AdCFTR experimental therapy. 
Method of Administration of the Vector 
Constraints 
(1) To confine delivery to the nasal epithelium, the major constraint is 
volume, limited to about 0.2 ml. 
(2) To the epithelium of the large bronchi, the major constraints are 
delivery and localization. It is possible to aerosolize adenoviruses. 
However, aerosolization carries with it containment problems. Direct 
instillation of the vector works in experimental animals and has 
minimal containment problems. For safety purposes, instillation should 
be to the right or left side (see above). Although "local" administra- 
tion to a segment of large bronchus is possible in large experimental 
animals by using endobronchial tubes with balloons and catheters, this 
would be very difficult in individuals with CF (e.g., risk of general 
anesthesia, achieving air exchange distal to the balloon without the 
risk of atelectasis, the balloons may damage the epithelium, higher 
risk for infection, etc.) 
(3) Since the disease is limited to the airway epithelium from the larynx 
to the small bronchioles, it would be preferable to limit, as much as 
possible, the delivery of the vector to the airways and not to the 
alveolar epithelium. There is data that with direct instillation of 20 
ml of fluid to the human large airways, most of the fluid will stay in 
the airways and not reach the alveoli (Smith et al . , 1988). 
Conclusions Regarding Method of Administration of the Vector 
(1) Direct instillation to the right or left nostril, with limitation of 
volume to 0.2 ml. 
(2) Direct instillation to the right or left mainstem bronchus via a 
bronchoscope, with limitation of volume to 20 ml. 
Recombinant DNA Research, Volume 16 
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