A PHASE I STUDY OF AN ADENO-ASSOCIATED VIRUS-CFTR GENE 
VECTOR IN ADULT CF PATIENTS WITH MILD LUNG DISEASE. 
1.0 OBJECTIVES 
1.1 Primary Objectives 
Assessment of the safety of administration of a recombinant AAV-CFTR vector to 
the nasal epithelium and single lung lobe. Dose escalation will be performed in an 
attempt to achieve the maximum tolerated dose (MTD). 
1.2 Secondary Objectives 
Assessment of in vivo gene transfer of the AAV-CFTR vector. 
Assessment of CFTR gene expression and physiologic effect following 
gene transfer. 
Assessment of the clinical impact of CFTR gene expression following gene 
transfer. 
Monitor patient immune response directed against CFTR or vector components 
following vector administration. 
2.0 BACKGROUND 
Cystic fibrosis (CF) is the most common lethal inherited disorder in North America, having 
an autosomal recessive inheritance pattern with an incidence of 1 in 2750 live births 1. The 
hallmarks of the disease include thick, dehydrated airway mucus, chronic Pseudomonas 
lung infection, pancreatic insufficiency, bile duct obstruction, infertility in males, reduced 
fertility in females, high sweat Cl", intestinal obstruction, nasal polyp formation, and 
chronic sinusitis. A theory which unified all of the seemingly disparate abnormalities, 
suggested first by Quinton^, is that all epithelial cells affected by CF have defective C1‘ 
transport^. 
The CF gene has been cloned and sequenced and shown to encode a protein called the 
cystic fibrosis transmembrane conductance regulator (CFTR)4. It has been shown 
convincingly that CFTR functions as a Cl - channel with distinctive properties^. The CFTR 
protein is localized on the apical cell membrane and participates in Cl - transport. In tissues 
affected in CF, mutations in the CFTR gene result in defective functioning and processing 
of the protein causing the wide range of symptoms associated with CF. 
Over 300 mutations in the CF gene have been identified^; however, approximately 90% of 
the chromosomes carrying a CF mutation have a single three base pair deletion which 
results in a deletion of a phenylalanine at position 508 (AF508). The CFTR protein bearing 
the AF508 mutation is improperly trafficked to the cell membrane, probably due to 
abnormal folding of the protein and increased degradation in the endoplasmic reticulum^. 
The reduced quantities of CFTR which escape degradation and are properly transported to 
the plasma membrane display reduced Cl - channel function^. This compounding of miss- 
trafficking with reduced Cl - channel function is associated with severe phenotypes of CF. 
Recombinant DNA Research, Volume 20 
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