M.J. Welsh and A.E. Smith, RAC Application 
Not only are there advantages associated with the presence of E3; there may be 
disadvantages associated with its absence. Studies of E3-deleted virus in animals have 
suggested that they result in a more severe pathology (91). Furthermore, E3-deleted virus, 
such as might be obtained by recombination of an El plus E3-deleted virus with wild-type 
virus, is reported to outgrow wild-type in tissue culture (92). In contrast, however, a recent 
report of an E3 replacement vector encoding hepatitis B surface antigen, suggests that when 
delivered as a live enteric vaccine, such a virus replicates poorly in humans compared to 
wild-type (93). 
4.4 Safety of Adenovirus as a Gene Delivery System 
Adenoviruses have an impressive safety profile in clinical use. Serotypes 4 and 7 have 
been used as live enteric vaccines for many years with an excellent safety record; they have 
been used to treat military recruits to prevent epidemic acute respiratory disease (94,95). 
However, adenoviruses are regarded as tumor viruses in that injection of some strains into 
newborn rodents can cause tumors and infection of some nonpermissive cells can cause 
transformation of cellular growth (77). Of the different adenovirus subgenera, subgroup A, 
including Ad 12, is highly oncogenic in newborn animals; subgenus B including Ad7 is 
weakly oncogenic; and the other subgenera, including Ad2 and Ad5 of subgroup C, are 
considered non-oncogenic in that they have not been shown to induce tumors upon 
injection into animals (96,97), reviewed in 75,80). The region of the adenovirus genome 
associated with oncogenicity is the El region, encoding Ela with immortalizing activity 
and Elb with transforming ability. 
The following arguments lead us to believe that the oncogenic potential of adenovirus 2 
possesses little or no risk to human patients in the protocol proposed here: 
a. Ad2 belongs to subgenus C that is regarded as non-oncogenic. 
b. The genes with transforming potential have been deleted from our vector. 
c. Human use of the mildly oncogenic subgenus B Ad7 strain as a live, enteric, human 
vaccine has proved safe in millions of young adults over many years (94,95). 
d. Even the so called highly oncogenic strains of virus are not particularly efficient at 
causing tumors in rodents, requiring many millions of virus particles per event (80). 
e. No naturally occurring tumors in any animal have been shown to be caused by 
adenoviruses even though over 100 different avian and mammalian serotypes are known 
(80). 
f. An extensive survey of human tumors revealed no evidence of adenovirus DNA 
associated with neoplasia (75,98,99). 
4.5 Potential Disadvantages of Adenovirus for CF Gene Therapy 
Adenovirus has some potential disadvantages for gene therapy. 
a. Administration of the virus may induce an immune response. An immune response 
could reduce the efficacy of the virus by producing neutralizing antibodies. 
b. Of more immediate concern, an immune response could stimulate an inflammatory 
response to the virus which could exacerbate problems in lung function in patients who 
already have compromised activity. 
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Recombinant DNA Research, Volume 16 
