Recombinant DNA Advisory Committee- 9/12-13/94 
inflammatory responses occur in the first week and disappear after 10 days in cotton rats. 
This point is particularly pertinent in repeated inoculations. Bronchial alveolar lavage 
should be performed early after inoculation to determine if the vector induces any 
inflammation. Besides cytokines, cellular immunity plays a very critical part in the 
inflammatory response particularly with the E3-deleted adenovirus vectors. One of the 
gene products of E3 reduces the expression of Class I major histocompatibility (MHC) 
antigen on the cell surface, and thus reduces cellular immune response. The E3 deletion 
increases pathogenicity in cotton rats. 
Other Comments 
Dr. Parkman said that repetitive vector administration is a logical step toward clinical 
fruition in the CF study. Dr. Crystal’s original submission did include both single and 
multiple vector administration, although the latter was deleted. There were animal 
experiments for multiple vector administration, and they showed that the second dose of 
vector produced a more virulent inflammatory response. Since it is proposed to give 6 
repeat doses to humans, the minimum amount of animal data should include at least 6 
administrations. Repeat administration increases the cellular type of immune response. 
Ms. Meyers asked Dr. H. Ginsberg to clarify his assessment about the safety of the 
adenovirus vector. Dr. H. Ginsberg said that the vector does express the CFTR gene in 
animals and in humans. He was concerned about the safety problem because E3 deletion 
of the vector increases its pathogenicity, and this effect does not require virus replication 
even though the vector is a crippled virus. 
Dr. Ross stated that it would be more understandable to patients if the procedures and 
time schedules of the clinical protocol were summarized in a flow chart in the Informed 
Consent document. It would be particularly useful for a complicated protocol like this 
one. Ms. Meyers commented that this protocol has one of the best Informed Consent 
documents that she has reviewed. 
Dr. Marcel asked if patients’ seropositivity or seronegativity to adenoviruses should be 
listed in the exclusion/inclusion criteria. Dr. Parkman remembered this question has been 
asked when the RAC reviewed Dr. Crystal’s previous protocol, but it was deleted from the 
protocol. Dr. H. Ginsberg said that unless the antibody levels were extremely high, it 
would be unlikely that there would be a direct effect on adenovirus replication. 
Mr. Capron asked if Dr. Crystal would comment on the relative merit of the adenovirus 
vectors versus AAV vectors. 
Investigator Response-Dr. Ciystal 
Responding to the question about a flow chart. Dr. Crystal said that such a chart had been 
prepared and included in the appendix of the submission material. 
Regarding the question of immune status, Dr. Crystal clariGed that seropositivity is listed 
[40] 
Recombinant DNA Research, Volume 20 
