Recombinant DNA Advisory Committee - 03/1-2/93 
important difference between this protocol and Dr. Welsh's nasal administration protocol 
is the proposed doses of vector. Dr. Welsh's protocol proposed doses between 2 x 10 6 
and 5 x 10 7 pfu. In this protocol, patients will receive between 2 x 10 8 and 2 x 10 11 pfu. 
Dr. Post added that similar doses of adenovirus vector have been approved for other CF 
protocols. The unique feature of this protocol is that the vector particles will be 
administered in a relatively small volume, i.e., 2 ml. The investigators propose that this 
concentration of virus will result in a high multiplicity of infection (MOI), i.e., 1 x 10 4 
infectious viruses per cell. 
Dr. Post explained that he was originally concerned that this high MOI might increase 
the probability of generating replication-competent adenovirus which could result in a 
cytopathic effect. The investigators have provided extensive discussion with regard to the 
in vitro versus in vivo effects of high MOIs. The investigators have proposed a rapid 
dose-escalation, i.e., a 30-fold increase in concentration per group. Dr. Post asked the 
other RAC members to state their opinions about the proposed doses. The investigators 
have provided supplemental data derived from extensive baboon studies. These studies 
involved a total of 15 baboons that received intranasal administration of 1 x 10 11 virus 
particles. Analyses of these animals was still in progress at the time of the original 
submission; therefore, the investigators should provide an update on this in vivo data. 
Dr. Post asked about the status of vector sequencing. The investigators' written 
responses indicated that additional sequencing information would be available at this 
meeting. The RAC should consider whether complete sequencing of adenovirus vectors 
is a requirement. The RAC has always required that an investigator submit the vector 
sequence, yet the committee has never provided specific details. 
The investigators have proposed a very stringent assay for the detection of helper virus. 
In light of the discussion of Drs. Wilmott, Whitsett, and Trapnells' protocol, perhaps the 
assays proposed for this study are too stringent. What is the difference between helper 
virus assays #1 and #2? Which assay(s) will be performed? How is a determination 
made as to the cell types that are recovered by bronchial alveolar lavage (BAL)? Can 
respiratory epithelial cells be distinguished from infiltrating lymphocytes? 
Dr. Post complimented the investigators for submitting a well-designed, readable, and 
thoroughly documented protocol. He stated that if the investigators provide satisfactory 
responses to his questions, he would recommend approval of the protocol. 
Review— Dr. Motulsky 
Dr. Motulsky stated that the protocol has been thoroughly documented, and that he is 
very satisfied with the overall design of the study. The investigators should respond to 
several issues during their presentation. What is the possibility that patients will produce 
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Recombinant DNA Research, Volume 17 
