to to to to 
M.J. Welsh and A.E. Smith. RAC Application 
TABLE OF CONTENTS 
Page 
1.0 INTRODUCTION. 4 
.0 BACKGROUND AND RATIONALE. 5 
. 1 Morbidity and Mortality In Cystic Fibrosis. 5 
.2 Current Treatment of Cystic Fibrosis. 5 
.3 The CF Gene and Gene Product. 6 
3.0 CONSIDERATIONS FOR GENE THERAPY OF CF. 8 
3.1 Target Tissue. 8 
3.2 Delivery of CFTR cDNA. 9 
3.3 Efficiency of Gene Delivery Required to Correct the Genetic Defect. 9 
3.4 Effect of Overexpressing CFTR. 10 
3.5 Use of Retroviruses for CF Gene Therapy. 1 1 
4.0 USE OF ADENOVIRUS FOR CF GENE THERAPY. 1 1 
4. 1 Differences Between Adenovirus and Retrovirus Vectors for Gene Therapy. 1 1 
4.2 Advantages of Adenovirus as a Vector System. 12 
4.3 Design of the Adenovirus Vector. 13 
4.4 Safety of Adenovirus as a Gene Delivery System. 14 
4.5 Potential Disadvantages of Adenovirus for CF Gene Therapy. 14 
5.0 USE OF NASAL EPITHELIUM FOR STUDIES OF GENE THERAPY. 15 
6.0 IS THE USE OF AN ADENOVIRUS VECTOR SAFE? 16 
7.0 SPECIFIC AIMS. 18 
7.1 Assess Safety. 18 
7.2 Assess Efficacy. 18 
7.3. Assess the Effect of Dose. 18 
8.0 NIH POINTS TO CONSIDER. 19 
I. Description of Proposal 19 
A. Objectives and Rationale of the Proposed Research. 19 
1. Use of Recombinant DNA for Therapeutic Purposes. 19 
2. Transfer of DNA for Other Purposes. 20 
B. Research Design, Anticipated Risks and Benefits. 20 
1. Structure and characteristics of the biological system. 20 
2. Preclinical studies, including risk- assessment studies. 31 
a. Laboratory studies of the delivery system. 31 
b. Laboratory studies of gene transfer and expression. 35 
c. Laboratory studies pertaining to the safety. 47 
3. Clinical procedures, including patient monitoring. 57 
4. Public health considerations. 65 
5. Qualifications of investigators, adequacy of facilities. 67 
C. Selection of patients. 68 
D. Informed consent. 69 
E. Privacy and confidentiality. 71 
Recombinant DNA Research, Volume 16 
