(5) Clinical improvement? A variety of lung-related clinical parameters 
will be used to assess improvement relevant to the clinical status of 
the patient. 
(6) Does humoral immunity develop against the vector and, if so, will it 
prevent chronic administration in the future? From the in vivo data 
generated in experimental animals and the in vitro data showing cor- 
rection of the CF phenotype in epithelial cells derived from indi- 
viduals with CF, it is very likely that respiratory administration of 
the adenovirus vector containing the normal human CFTR cDNA should 
correct the CF phenotype at the biologic level. While it is likely 
that the correction may persist for a significant period, the fact 
that the adenovirus does not transfer genes to the genome of most 
target cells, and the normal turnover (albeit slow) of the respira- 
tory epithelium, suggest that therapy will have to be periodic. In 
this case, it is an important goal of this protocol to define the 
humoral immune response to respiratory administration of the vector. 
This will be defined in the serum and lung epithelial lining fluid by 
periodic measurements. If anti-vector antibodies are detected, they 
will be evaluated for their neutralizing activity (if any) in 
regards to the ability of the vector to infect and transfer the CFTR 
cDNA to human epithelial cell lines and freshly isolated human 
respiratory airway epithelial cells. This will be evaluated with 
serum and epithelial lining fluid sampled over time after the 
administration of the vector. 
In the design of this protocol it is recognized that with the limited number 
of individuals to be studied (n=10) and/or the doses used for only n=2 at each 
dose, that no biologic efficacy may be detected. If no biologic efficacy is 
detected and there are no safety problems associated with the AdCFTR vector, 
the approving committees will be asked to allow the number of study 
individuals to be increased. 
5.8 Additional Safety Issues 
5.8.1 Health Care Workers 
During the baseline and vehicle control periods, there are no additional 
safety issues for health care workers beyond those for usual clinical proce- 
dures for the evaluation and care of individuals with cystic fibrosis. During 
the AdCFTR experimental therapy period, the health care workers will be 
exposed to no additional safety concerns beyond those for dealing with 
patients with infectious virus infection that can be spread by the respiratory 
and/or oral- fecal routes. Recommendations of the NIH Biosafety Office will be 
followed for handling patients, biologic materials, bedding, towels, etc. 
Appropriate training sessions developed by the Pulmonary Branch, NHLBI in 
conjunction with the NIH Biosafety Office will be used to educate all health 
care workers as to the protocol and relevant hazards, precautions and 
procedures . 
5.8.2 Environment 
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