Recombinant DNA Advisory Committee - 12/2-3/93 
related injury. 
Investigator Response-Dr. Welsh 
Dr. Welsh responded to the RAC's concerns about the patient isolation period. Patients 
were isolated for 5 to 6 days in the previous study. This period of time presented several 
serious problems to the CF patients. Their clinical symptoms were adversely affected by 
their lack of daily exercise. Patient recruitment was difficult due to the reluctance of 
these patients to remain in the hospital for almost one week a month while enrolled in 
the protocol. A prolonged isolation period is unnecessary because these vectors are 
replication-deficient. In addition, the proposed new vector contains an E4 deletion that 
limits its survival outside of the patient's body. Despite the extensive use of these 
vectors in many laboratories, there have been no instances of adverse consequences to 
laboratory personnel or health care workers. In an unrelated study in which army 
personnel were inoculated with wild-type adenovirus, the rate of horizontal transmission 
in these subjects was extremely low. Other investigators have published monkey studies 
in which a low rate of horizontal transmission was demonstrated. At a previous RAC 
meeting, Dr. Harold Ginsberg of Columbia University (an ad hoc reviewer for the initial 
CF studies) indicated that the chance of these impaired viruses surviving outside of the 
clinical setting is extremely low. The IRB has included the requirement that health care 
workers will be assayed for immunologic responses to these viruses. 
Ms. Grossman asked if the proposed vector poses little risk, why will patients be isolated 
for 24 hours? Dr. Welsh responded that this time period is for the purpose of patient 
observation. Dr. Miller commented that the half-life of the virus, approximately 2 
minutes at 46° C ex vivo , is relatively short; therefore, a short isolation period is justified. 
Dr. Welsh said that complete vector clearance was observed within one day in the 
previous study. Dr. Miller suggested that the RAC approve the protocol contingent on 
the stipulation that if virus is detected within 24 hours in a single patient, the isolation 
period should be extended. Although there are no major safety concerns associated with 
adenovirus shedding, the RAC should maintain public confidence about gene transfer 
studies by ensuring the lack of virus shedding. Ms. Grossman stated that although she 
has provided comments regarding the proposed study, she will abstain from voting on the 
protocol due to conflict of interest (co-investigator on another RAC-approved CF 
protocol). 
Dr. Welsh said that the unexplained death of some animals in the preclinical studies was 
unrelated to gene therapy, noting that the control animals developed symptoms. All 
animals (male and female) were from a single lot of animals. If the new PGK promoter 
proves to be more efficacious than the previous promoter, a request for a minor 
modification will be submitted as suggested by Dr. Post. 
In response to Ms. Grossman's question about the lack of difference in gene expression 
between single versus multiple vector administration in cotton rats, Dr. Welsh explained 
that the context of the experiment was misunderstood. In monkey experiments, the same 
level of expression of the reporter gene was observed even after 5 administrations of the 
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Recombinant DNA Research, Volume 18 
