Recombinant DNA Advisory Committee - 12/2-3/93 
There was no evidence of shedding of replication-competent adenovirus from any of the 
treated patients. A dose-dependent induction of complement fixation antibodies was 
demonstrated; however, no induction of neutralizing antibodies was observed in treated 
individuals. Patient 2A, who received the highest concentration of vector, developed a 
mild reaction. This 24 year-old female received a dose of 2 x 10 7 efu to the nasal 
epithelium, and 24 hours later she received 2 x 10 9 efu to the right lower lobe bronchus. 
She exhibited symptoms of fatigue for 5 to 7 days, intermittent fever for 6 days, 
hypotension, hypoxemia, and lung infiltrate in the right lower and middle lobes. 
Although the vector was administered to the lower lobe, infiltrate in the right middle 
lobe was confirmed by a chest X-ray. All reactions were transient and disappeared after 
symptomatic treatment. The single adverse effect was probably due to vector-induced 
inflammation of the lung. Other possible causes have been eliminated, such as pathology 
of the disease itself, complication of bronchoscopy, contamination of the vector 
preparation, and complementation or recombination of vector with other adenovirus 
strains. No adverse reactions were observed in the preclinical animal studies. 
The efficacy data are incomplete at this time. CFTR gene expression was demonstrated 
in the nasal epithelium; however, functional data demonstrating correction of the CFTR 
deficiency in the nasal epithelium are suggestive but less conclusive. The present data 
defines a range of toxicity that will allow for the design of future experiments. Lower 
starting doses will be initiated in order to explore a dose range that will prove to be 
efficacious. 
Dr. Miller asked whether any adverse reactions were observed in the monkeys following 
repeat vector administration. Dr. Crystal responded that no responses were observed in 
monkeys. These reactions may be specific to CF patients whose lungs already have 
abnormalities. Dr. Crystal explained that the volume of the vector has been reduced 
from 20 ml to 5 ml for lung administration to avoid the possibility of alveolar 
inflammation. The adverse event was reported to the RAC, IRB, FDA, and other 
investigators conducting CF gene transfer trials. Similar dose adjustments have been 
made in other CF trials. 
XIX. ADDITION TO APPENDIX D OF THE NIH GUIDELINES REGARDING A HUMAN 
GENE TRANSFER PROTOCOL ENTITLED: GENE THERAPY FOR CYSTIC 
FIBROSIS USING CATIONIC LIPOSOME MEDIATED GENE TRANSFER : A PHASE 
I TRIAL OF SAFETY AND EFFICACY IN THE NASAL AIRWAY/DRS. SORSCHER 
AND LOGAN 
Review-Dr. Post 
Dr. Walters called on Dr. Post to present his primary review of the protocol submitted 
by Drs. Eric J. Sorscher and James L. Logan of the University of Alabama, Birmingham, 
Alabama. Dr. Post explained that the objective of this proposal is to evaluate cationic 
liposome-based delivery of the CFTR gene to nasal respiratory epithelia of CF patients. 
The nasal airway epithelium is an ideal model for gene transfer since this epithelium 
exhibits a CF bioelectric defect and is easily accessible for safety and efficacy studies. 
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Recombinant DNA Research, Volume 18 
