Recombinant DNA Advisory Committee - 12/3-4/92 
Review~Dr. Post 
Dr. Murray called on Dr. Post to present his primary review of the protocol submitted by 
Dr. Michael J. Welsh of the Howard Hughes Medical Institute, University of Iowa 
College of Medicine, Iowa City, Iowa. Dr. Post said that most of his original concerns 
have already been addressed and resolved during the presentation of Drs. Crystal and 
Wilson's protocols. Therefore, he said that he would keep his comments to those issues 
that are significantly different from the previously reviewed CF protocols. 
The most significant difference about this CF protocol is that the virus will be applied to 
the nasal epithelium of the patient, not the lung. Nasal administration provides the 
added assurance that if untoward effects occur, e.g., an inflammatory response, the 
consequences will be less severe than effects that might occur in the lung. In regard to 
efficacy, the investigators will have more direct access to the transduced tissue. 
The investigators propose to use a Type 2 adenovirus-based vector rather than a Type 5 
adenovirus. Dr. Welsh has stated that the decision to use the Type 2 virus was arbitrary. 
The proposed vector has retained the E3 gene. Although the increased size of the 
vector has compromised yield, there are no longer concerns about the possibility of an 
inflammatory response to the vector that is greater than wild-type virus. 
Due to the localized administration of this therapy, the dosages will be less than those 
proposed for the lung administration protocols. Patients will receive 3 doses that will 
escalate from 2 x 10 6 PFU to a maximum dose of 5 x 10 7 PFU. 
Preclinical animal studies have been performed in monkeys, hamsters, and cotton rats. 
In vivo safety and efficacy experiments demonstrated efficient transduction of the nasal 
epithelium and only mild inflammation at doses that were significantly higher than those 
proposed for the human protocol. Virus detection in secretions and excretions was 
observed for only a few days. 
Dr. Post noted that the DNA sequence of the entire vector was not provided. The DNA 
sequence that was provided by the investigators was that of the starting plasmid. 
Approval of the protocol should be contingent on the review of this sequence. Dr. 
Welsh has stated that he will submit the entire vector sequence when it becomes 
available. 
Dr. Post stated that the detection of Ela sequences is probably easier in this protocol 
than for the other CF protocols because the total number of viral particles is significantly 
less. The PCR assay proposed by Dr. Welsh will detect 20 Ela positive adenovirus 
particles in a background of 10 9 particles. This level of sensitivity will detect 1 particle in 
Recombinant DNA Research, Volume 16 
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