TABLE OF CONTENTS 
Page 
I. Abstract 4 
II. Background 5 
A. Cystic Fibrosis (CF) 5 
1. Pathogenesis 5 
2. Organ-specific pathophysiology 6 
3. Clinical aspects 7 
4. Treatment 9 
B. Gene Therapy for CF Lung Disease 9 
1. General 9 
2. Target for CF Lung Gene Therapy 10 
3. Strategies 11 
4. Efficiency 13 
C. The nose as a model of CF dysfunction 14 
D. Xenograft model 16 
III. Adenovirus construct 18 
IV. Pre-Clinical Studies 21 
A. Efficacy 21 
1. Gene transfer to airway epithelia - general 21 
2. Adenovirus-mediated gene transfer 22 
a. Reporter gene (lacZ) expression 22 
i. Cultured cells - mouse and human 22 
ii. Xenografts 26 
iii. Mice in vivo 32 
b. CFTR phenotypic correction in vitro 34 
c. Complementation in human CF xenografts 39 
B. Safety 41 
1. Studies of acute injury 41 
a. Mouse 41 
b. Non-human primate 43 
2. Ectopic expression 46 
3. Overexpression of CFTR 47 
a. Transgenic mice 47 
b. Level of expression - CFT1 cells 48 
c. Apical membrane Cl' conductance - CFT1 cells 50 
4. Effect on barrier function of epithelia 50 
5. Biology of recombinant adenovirus 52 
6. Germ line transmission 56 
7. Recombination 56 
8. Malignancy 56 
9. Integration 56 
10. Immune response 56 
Recombinant DNA Research, Volume 17 
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