gene transfer and correction of the defective CF-related airway epithelial cell 
function can be corrected. The design of the current study makes it highly likely 
that at least some of this information will be forthcoming. These results will play a 
key role in the design of future studies that address delivery of the gene to the 
tracheobronchial tree. A lack of success in correcting the CF cell dysfunction, or 
evidence of a substantial inflammatory response (particularly if persistent), will 
provide a clear impetus for pursuing the design and development of alternative 
vectors for gene therapy of CF. Alternatively, successful correction with little 
adverse effect will set the stage for a study to see if repetitive correction can be 
achieved. 
V.F. Risk/benefit ratio for these studies: 
The risks of this study are largely related to the possibility of (1) 
inflammatory and immunological responses that are of sufficient magnitude and 
duration to be of concern; (2) replication of the virus; (3) risk of environmental 
spread of the recombinant virus; and (4) risks associated with study procedures. 
(1) Inflammation and immune response: Local inflammatory and/or 
cytopathic effects are possible at the site of application of the virus. These 
possibilities include pain, mucosal edema and inflammation, and bleeding, although 
it is unlikely that serious long-term effects will occur. We have attempted to limit 
these risks by the use of small doses of virus in a limited area of nasal epithelium 
and the use of dose-escalating study design. We have selected the nasal epithelium 
as the site of initial challenge (rather than the tracheobronchial tree) as an 
additional safety feature, i.e., this study design will not threaten respiratory status. 
Another type of risk relates to the possibility of these study subjects not being able 
to receive subsequent adenoviral-mediated gene therapy to the tracheobronchial 
tree, i.e., it is possible that additional administration of an adenoviral vector could 
generate an immune response that would prevent subsequent treatment in the lower 
respiratory tract with the adenoviral CFTR vector. Although possible, it seems that 
this would be more likely to occur in patients who are seronegative to the 
adenovirus type 5, or perhaps patients who have repeated exposures to the virus. 
(2) Viral replication: Although the adenoviral vector has been rendered 
defective for replication by deletion of a segment of the El region, it is possible that 
the virus may have some ability to replicate in human airway epithelium. It is also 
possible that super-infection with a wild type adenovirus, or provision of the missing 
El and E3 sequences by a latent or residual adenovirus from an earlier infection, 
could complement the recombinant virus and provide replication competency. On 
balance, however, these possibilities seem unlikely to occur or to produce significant 
complications. 
Another possibility is recombination of Ad5-CB-CFTR and a wild type 
adenovirus. The most likely combination event would occur between a segment of a 
wild type sequence 3’ to the CFTR gene. This recombinant would form two viruses: 
one containing the CFTR minigene, but this would exceed the wild type viral 
genome size and (to date) we have not been able to make this virus; and the second 
viral recombinant would be a wild type virus missing the E3 sequences, a construct 
that should not be any more pathogenic than either parent virus. Second, the 
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