M.J. Welsh and A.E. Smith, RAC Application 
7.0 SPECIFIC AIMS 
The foregoing considerations indicate that gene therapy would be a major advance in the 
treatment of CF. They also suggest that adenovirus may be a good vector system for 
correcting the CF pulmonary defect. In section 8.0 (the NIH Points to Consider), we 
provide data that a recombinant adenovirus encoding CFTR can be used to complement the 
CF airway epithelial electrolyte transport abnormality. We also provide safety data for the 
vector. 
Thus, we believe that it is now appropriate to test the feasibility of gene therapy in CF 
patients. We believe an appropriately designed protocol which uses minimal amounts of 
adenovirus and which is designed to minimize the risk to the patients is of critical 
importance in directing future research. Other approaches might be taken to introduce 
DNA into the airway cells of CF patients if adenovirus proves ineffective. On the other 
hand, there are many future generations of adenovirus that can be envisaged that would 
improve its properties as a gene delivery vector. Thus, there is an urgent need for data in 
humans to guide which direction future research should take. We believe the present 
protocol would provide such guidance, but at the same time, minimize any possible risk to 
the patient. 
There are three specific aims of the proposed study. 
7.1 Assess safety of the current recombinant adenoviral vector/CFTR gene construct when 
applied to human airway epithelium in vivo. This aim will assess the possibility that the 
recombinant virus will produce local inflammation or injury of the airway epithelium. It 
will also determine the time after administration that the live virus disappears from the 
nasal epithelium and will test for any possible subsequent virus replication. 
7.2 Assess efficacy of the recombinant adenoviral vector/CFTR gene construct in human 
airway epithelium in vivo. This aim will assess the ability of the viral construct to deliver 
the cDNA for CFTR to respiratory epithelium in vivo, the ability of the transferred cDNA 
to direct the expression of CFTR protein, the ability of that process to correct the CF 
chloride transport defect, and the duration of these effects. 
7.3. Assess the effect of dose of recombinant adenoviral vector/CFTR gene construct on safety 
and efficacy. 
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Recombinant DNA Research, Volume 16 
