cation competent adenovirus that is E3~ (Figure 4.9-B). The chances of this 
occurring in the respiratory tract following AdCFTR administration in 
humans with CF is not possible to estimate. However, there are ways to 
minimize this from occurring. Further, if this should occur, the outcome 
will likely be no worse and possibly less serious, than that of an infec- 
tion with a naturally occurring adenovirus. 
First, the Ela sequences would have to be exogenous, as the individuals 
with CF will be screened to insure that they are Ela" in their respiratory 
tract. To form the basis of this concept, individuals with CF and controls 
were evaluated for the presence of Ela (Table 4.9-B). Importantly, only 10% 
were positive; of these individuals, there was an average of 87^26 copies 
of Ela/10 3 airway epithelial cells (Table 4.9-B). The concept of using Ela" 
epithelia as a criteria for entry into the protocol is discussed in further 
detail in Section 5.3.4. 
Second, to further insure that the Ela sequences would have to be exoge- 
nous , the individuals with CF will be screened to insure that they are not 
harboring active respiratory viruses in the respiratory epithelium. Screen- 
ing of such patients demonstrates that harboring such viruses is rare (only 
herpes simplex was found among several virus types, and herpes simplex was 
only found in 2 of 29 individuals, Table 4.9-C). Thus, negative cultures 
for active virus in the respiratory tract will be used as an inclusion 
criteria for the protocol (see Section 5.3.2). 
Third, to minimize Ela sequences from exgenous sources (e.g., adenovirus 
infection) , the individual will be kept under gown and glove respiratory 
precautions (see Section 5.6) for 10 days before and after therapy, and 
insuring no contact with children under the age of 15 (the most likely ages 
for transmission of respiratory viruses). Further, no individual will be 
treated that has signs or symptoms of a respiratory tract infection. 
Fourth, replication competent wild type E3 _ adenovirus has been used in 
humans in vaccine trials (see Section 4.8), with actually less shedding 
than with the wild type E3 + adenovirus . 
Finally, an E1“E3 _ Ad5 -based vector containing the human CFTR cDNA sup- 
presses the replication of replication competent Ad5 (Figure 4.9-A), simi- 
lar to that observed with an E3~ replication competent adenovirus co- in- 
fected with an E3 + replication competent adenovirus. 
Ongoing studies with cotton rats and rhesus are being carried out to deter- 
mine the consequences of exogenous replication competent adenovirus being 
made available to the respiratory epithelium of experimental animals previ- 
ously treated with an E1~E3~ adenovirus vector, i.e., are there adverse 
clinical consequences of exposure to replication competent adenovirus in 
the circumstance where there has been prior administration of a vector of 
this design? 
Cotton rats were treated with AvlCFl (intranasal 10 xo pfu/kg) . After 1 
week, they were then exposed to Ad5 (10 9 pfu/kg) (study CRCW.003). In the 
group treated with AvlCFl followed by Ad5 , 8/9 animals survived over the 3 
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