Recombinant DNA Advisory Committee - 12/2-3/93 
approaches that provide informative results. These trials complement each other. The 
documentation submitted in support of this proposal is superb. Dr. Post commended the 
investigators for providing a thorough report on the results of the first trial. Data from 
the cotton rat experiments indicate that large doses of the adenovirus vector can cause 
inflammation. This in vivo data, in addition to Dr. Crystal's report on a possible adverse 
effect, supports the strategy of characterization of these vectors in the upper respiratory 
tract prior to lung administration. 
Dr. Post stated that the investigators provided excellent responses to the questions 
presented in his primary review. He asked the investigators to respond to the following 
additional comments: (1) The investigators propose to use a new adenovirus vector in 
which a PGK (phosphoglycerate kinase) promoter is used to permit sustained low level 
CFTR expression. Is there any evidence that the limited duration of CFTR expression 
with the previous vector is due to promoter shut-off, as opposed to loss the vector DNA? 
(2) The investigators state that the possibility of recombination of the new types of 
adenovirus sequences with the 293 vector producer cells is lower than with the new 
vector than the previous vector. Has the new vector been subjected to the same level of 
safety testing as the previous vector? (3) In what volume will the vector be administered 
to the nose versus the maxillary sinus? Have any precautions been introduced to prevent 
spillage? Dr. Welsh responded that 0.5 ml will be used. The maxillary sinus is self 
contained; therefore, spillage is not a significant problem. (4) Have preclinical 
experiments been conducted demonstrating the ability to administer the vector to the 
maxillary sinus? (5) The investigators have stated that patients with active adenovirus 
shedding within 3 weeks will be excluded from the study to avoid recombination with 
wild-type virus. What is the exact period of time indicated by this statement? Dr. Welsh 
responded that patients demonstrating positive adenovirus cultures 3 weeks prior to the 
start of the experiment will be excluded from the study. (6) When and how after will 
biopsies be performed? (7) The subjects will be isolated for 24 hours following vector 
administration based on the previous observation that virus shedding was absent after 
this period of time. However, this proposal involves a 200 fold increase in the amount of 
virus administered. Will this period of isolation be adequate for these increased doses? 
Dr. Welsh responded that isolation periods greater than 24 hours may be detrimental to 
CF patients. CF patients must maintain a daily exercise routine. Dr. Post agreed that 
lack of exercise is a reasonable consideration, but cautioned that the monitoring of virus 
shedding is an important safety issue. However, it is most likely that the recombinant 
vector does not pose increased risk over the wild-type virus. (8) What proportion of 
each vector lot will be assayed for wild-type adenovirus? Dr. Welsh has indicated his 
intention to request permission to introduce the same promotor used in this vector, 
PGK, into other adenovirus vectors as outlined in the protocol. These changes would be 
submitted to the RAC as minor modifications to the current proposal. Dr. Post stated 
that he would recommend approval of such modifications. 
Review-Dr. DeLeon 
Dr. DeLeon complimented the investigators on this well-documented protocol. The 
rationale and schema for the proposal is logical, the end points are clearly defined, and 
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Recombinant DNA Research, Volume 18 
