Recombinant DNA Advisory Committee - 12/3-4/92 
concern? Dr. Leventhal asked if the investigators plan to perform any follow-up studies 
on the health care providers of these patients regarding the transmission of the virus. 
Presentation-Dr. Crystal 
Dr. Murray called on Dr. Crystal to respond to the questions and comments presented by 
the RAC members. Dr. Crystal provided an overview on CF, the most common lethal 
hereditary disorder of Caucasians and, to a lesser extent, Hispanics. CF pulmonary 
disease causes a thick, sticky mucus that results in chronic infection, inflammation, and 
airway obstruction. CF is a progressive disease; the average life span of a CF patient in 
the United States is approximately 29 years. The problems associated with the 
gastrointestinal tract are manageable. The majority of CF male patients are infertile. 
Current therapy for CF disease involves mechanical approaches to airway clearance, i.e., 
antibiotics, pancreatic enzyme replacement, and nutritional supplementation. 
The mutations in the CFTR gene of these patients causes epithelial ion channel 
abnormalities that result in disease; however, the mechanisms are not clearly understood. 
An adenovirus vector was chosen for the transfer of the corrected gene because high 
titers of virus are obtainable and host cell proliferation is not required. The receptor for 
the adenovirus vectors has not been identified. The vector enters the endosome which 
has a low pH. It is in this endosome that the virus probably sheds it's coat and interacts 
with the nucleus; however, the majority of the vector probably works extra- 
chromosomally. 
Dr. Crystal presented in vivo data from the cotton rat model regarding transmission of 
the vector to the various parts of the airways. Histological examination demonstrated 
100% gene expression as far as the terminal bronchioli and alveoli in these animals. 
The proposed vector, AdCFTR, was constructed by Drs. Michel Perricaudet and Chin 
Chu. This vector is based on an E3-deleted, El-deleted adenovirus. Approximately 35 
to 40% of the Elb region is remaining in addition to the CFTR cDNA 
Dr. Crystal addressed the issue of vector safety. Historically, replication-competent 
adenoviruses have been administered to humans for a variety of reasons. In the early 
1960s, adenovirus infections were a major problem for closed populations and the 
military; therefore, live Type 4 and Type 7 vaccines were developed and marketed to the 
military. It is estimated that over 5 million doses of live adenovirus vaccine have been 
administered to date with no epidemiologic consequences. Other investigators have 
documented the intra-muscular, intra-cervical, intra-arterial, intravenous, and intra-nasal 
administration of live adenoviruses. Results indicate that in patients with pre-existing 
anti-adenovirus serum antibodies, clinical sequelae are mild and rare. Therefore, the 
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Recombinant DNA Research, Volume 16 
