believe it unlikely that replication of Ad5-CB-CFTR will occur in 
immunocompetent hosts. We will limit our trials to immunocompetent CF patients 
and include steroid use as an exclusion criterion. 
It is important to consider the consequences of the unexpected dissemination 
of the recombinant virus or a replication competent derivative. Previous experience 
with adenoviruses in humans suggests that they are relatively benign. Adenoviruses 
are endemic in the population causing a variety of self limited infections. Infection 
with Ad5 causes mild respiratory infections characterized by coryza, pharyngitis, 
fever, malaise, and tonsillitis. The relative safety of adenoviruses was evaluated in a 
series of experiments, performed in the late 1960’s and early 1970’s, in which 
volunteers were exposed via the respiratory tract to wild type forms of adenoviruses 
including the serotype used in this study (Ad5). For example, in a study by Couch et 
al. (92), normal adult volunteers were immunized to Ad5 capsid antigens and 
subsequently exposed to an inoculum of live Ad5 into the respiratory tract. Ten of 
19 individuals who received a placebo immunization and subsequently live Ad5 had 
a self limited febrile illness characterized by fever and moderate pharyngitis. No 
significant untoward effects were noted. 
An additional consideration relates to the malignant potential of these gene 
transfer reagents. In contrast to retroviruses which integrate into the genome, 
adenoviruses are maintained in the genome as extrachromosomal elements which 
theoretically cannot cause a secondary malignancy due to insertional mutagenesis. 
In support of this is the fact that no human malignancy has been directly linked to 
adenoviruses. 
Psychological and social implications. It is likely that the initiation of these 
experiments will be associated with tremendous attention by the media. We will 
follow a strict code of confidentiality as mandated by the RAC and inform the 
patients of this potential problem. 
VII.B. Risks to others 
The only potential risk to others is the possibility that the recombinant virus 
could be transmitted to another individual, take up residence, and cause disease. 
We believe this is highly unlikely for a variety of reasons. 
One very important aspect of this scenario relates to the likelihood that 
transmission of Ad5-CB-CFTR will cause disease. We obviously do not think this is 
likely based on the fact that we are proposing to use it therapeutically. Toxicity 
could be due to one of two mechanisms: expression of CFTR or pathology due to 
the inherent properties of Ad5. As we argued above, unregulated overexpression of 
CFTR does not appear to be toxic. Furthermore, pathology of the recombinant 
virus due to its properties as an infectious virus is unlikely because all patients will 
have had previous immunity to the virus and the recombinant should have a 
tremendous growth disadvantage due to the deletion of El. 
Recombinant DNA Research, Volume 17 
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