Recombinant DNA Advisory Committee - 12/3-4/92 
Since the discovery of the CFTR gene, investigators have demonstrated that the normal 
CFTR gene can be inserted into the cells of CF patients in vitro, and that these 
transduced cells are capable of normal function. Specifically, the corrected cells have the 
capacity to pump chloride ions, resulting in the normalization of the export of water. 
This observation suggests that correction of the defective CFTR gene in vivo would result 
in thinning of the patient's secretions. The objective of this protocol is to normalize the 
genetic defect in a significant number of bronchial cells so that the secretions obtain 
normal viscosity. Ultimately, the incidence of pulmonary infection would be decreased, 
and the patient's life would be prolonged. 
This protocol is very restricted in its clinical application. Ten patients will be enrolled, 
each receiving only a single vector application. Since bronchial epithelial cells have a 
short life span, only surface epithelial cells will be affected. Therefore, the benefits of 
this therapy, if any, will be restricted to the life span of these surface epithelial cells. 
Patients will be treated in groups of two. Each consecutive pair of patients will receive a 
1 log increase in dose of adenovirus vector; the lowest dose will have a titer of 10 6 
plaque forming units (PFU) and the highest titer will be 10 10 PFU. The objectives of 
this study are to demonstrate: (1) the efficient transduction of bronchial epithelial cells 
with the CFTR gene, and (2) the length of time that gene expression will persist and in 
what proportion of the cells. The information obtained from this study is necessary 
before the investigators can submit a multiple administration protocol. 
The investigators have a large amount of preclinical data to support this study. While 
their original experiments were performed using two adenovirus constructs, the most 
recent experiments have focused on one vector. Using this construct, the investigators 
have demonstrated the in vitro transduction of bronchial epithelial cells and nasal 
mucosal cells obtained from CF patients. In vivo expression of the CFTR gene has been 
demonstrated in both the monkey and cotton rat models. 
The protocol is divided into 3 parts: (1) the initial baseline period, (2) the vector control 
period, and (3) the experimental period. The baseline period is the timeframe that 
individuals are observed in order to determine if they have mild, moderate, or severe 
disease. Patients with severe disease will probably not be able to tolerate some of the 
procedures such as bronchoscopy; therefore, they will be ineligible for the protocol. 
Once a patient has been determined to satisfy the inclusion and exclusion criteria, 
he/she will enter the vector control phase. During this phase, patients will receive 
repeat administration of the media (vehicle) that will contain the vector. This vehicle 
control will be applied initially to the nares; and finally, a 20 ml administration will be 
applied to the left main stem bronchus. If no adverse effects are observed as result of 
the vehicle challenge, the patient will be qualified to proceed to the experimental portion 
of the protocol. During this phase of the study, the patient will receive a 0.4 ml 
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Recombinant DNA Research, Volume 16 
