M.J. Welsh and A.E. Smith, RAC Application 
8.0 NIH POINTS TO CONSIDER 
I. DESCRIPTION OF PROPOSAL 
A. OBJECTIVES AND RATIONALE OF THE PROPOSED RESEARCH. 
State concisely the overall objectives and rationale of the proposed study. Please 
provide information on the specific points that relate to whichever type of research is 
being proposed. 
The overall objectives of the proposed study are to use a recombinant adenovirus to deliver 
CFTR to the nasal epithelium of CF patients to: a) assess the safety of this adenovirus 
vector when applied to human airway epithelium in vivo ; b) assess the efficacy in 
correcting the chloride transport defect in vivo\ and c) assess the effect of dose of 
recombinant adenovirus on both safety and efficacy. The results will also provide guidance 
for the future direction of CF gene therapy. 
The rationale for the proposed study is as follows: CF is the most common lethal genetic 
disease of Caucasians (1-3). Despite current standard therapy of CF, the median age of 
survival is only 26 years. CF is caused by mutations in the gene encoding CFTR (4-6). 
Recently obtained knowledge of the gene that encodes CFTR, an understanding of the 
function and biochemistry of the protein product (7), and insight into the molecular basis of 
the disease (32,48,57-59), suggests that gene replacement therapy could represent an 
important advance in the treatment of this disease. Eventually, we hope to use recombinant 
adenovirus to deliver CFTR to the airway epithelium. In our initial studies, we will target 
the nasal epithelium, because it will allow us to test both efficacy and safety with the least 
risk to the patients. 
A.l. Use of Recombinant DNA for Therapeutic Purposes . 
Our present protocol will not be of therapeutic benefit to the participants. Correction of the 
genetic defect is likely to be limited to the area of virus application in the nose and to be 
transient. However, we believe the information obtained from this study regarding safety, 
efficacy, and dosing are critical before studies of bronchial administration can be safely 
performed. They will also guide the design of future generations of adenovirus. 
A.l.a. Why is the disease selected for treatment bv means of gene therapy ? 
Despite current standard therapy, CF remains a lethal disease. There is no treatment that 
corrects the basic defect. Nevertheless, the location of the target tissue, the understanding 
of the biology of CFTR, and the vector/delivery system provide an excellent opportunity 
for safe gene replacement therapy. 
A.l.b. Describe the natural history and range of expression of the disease selected for 
treatment What objective and/or quantitative measures of disease activity are 
available? In your view, are the usual effects of the disease predictable enough to 
allow for meaningful assessment of the results of gene therapy? 
We describe the natural history in Section 2.1. Disease activity is routinely measured with 
history and physical examination, chest X-rays, pulmonary function tests, and sputum 
cultures. The basic defect in the airway epithelium can be assessed biochemically and 
functionally by measurement of the transepithelial electrical potential difference across the 
nasal epithelium (103,104). The biochemical defects to be measured here are very 
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