Recombinant DNA Advisory Committee - 6/9-10/94 
following modifications: (1) the statement that the adenovirus vector "cannot cause 
disease" should be deleted, (2) the incomplete sentences should be corrected, and (3) the 
ambiguous statements regarding medical costs should be revised such that these issues 
are clearly disclosed. Dr. Straus concluded that approval is recommended contingent on 
incorporation of the suggested revisions. 
Review-Mr. Capron (presented by Dr. Haselkorn) 
Dr. Haselkorn stated that Mr. Capron provided a very detailed written analysis of the 
protocol. Mr. Capron states that the preclinical studies sufficiently justify the human 
trial. The injection of the recombinant adenovirus does not pose an unacceptable risk to 
other individuals who may come in contact with these subjects. Mr. Capron raised 
several questions about the number of patients entered on the study and the statistical 
design. He recommended several changes in the Informed Consent document for 
clarification. 
Review-Ms. Meyers (presented by Dr. Haselkorn) 
Dr. Haselkorn presented Ms. Meyers' written concern about the Informed Consent 
documents regarding medical costs and life-long follow-up. Ms. Meyers questioned 
whether 21 patients are justified for this Phase I trial. 
Review-Dr. H. Ginsberg (Ad hoc) 
Dr. H. Ginsberg commented on the biology of the adenovirus construct. One advantage 
of the proposed construct is that the inserted p53 gene replaces the Elb viral gene, thus 
preventing the complex formation between p53 and the 55 kilodalton Elb protein. He 
noted; however, that the cell transduction at a high multiplicity of infection may augment 
the expression of early genes. This vector is not a totally defective virus. He expressed 
concern that the pathogenicity of the virus has not been considered. Although viral 
DNA expression is required for the pathological response, the vector can produce severe 
pathogenic effects in cotton rats, mice, and non-human primates. Pathogenicity must be 
assessed prior to administering this construct to patients with pulmonary disease. One 
advantage of this vector over previous adenovirus vectors used in CF protocols is that the 
early region 3 (E3) has been retained that helps protect the cells from cytopathic effects. 
In regard to the issue of potential pathogenicity. Dr. H. Ginsberg explained that some 
animal models do not demonstrate clinical signs of adenovirus infection similar to 
humans; therefore, the choice of an animal model is important. The cotton rat is the 
model of choice because clear pathogenic effects of adenovirus infection are evident. 
Adenovirus pathogenic effects do not require viral replication. If large doses of 
adenovirus vector are administered, expression of early genes can produce such effects in 
the absence of viral replication. Pathogenicity is first observed in the alveoli followed by 
peribronchial and perivascular infiltration. Epithelial cells are not affected; therefore, 
epithelial cell brushings are inadequate to test for pathogenicity. There should be 
histologic examination of the tissue. Because the vector does not replicate, large doses 
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Recombinant DNA Research, Volume 19 
