Jy. Dong et al., SYSTEMATIC ANALYSIS OF REPEATED GENE DELIVERY INTO ANIMAL LUNGS WITH A RECOMBINANT ADENOVIRUS VECTOR, Human gene therapy, 7(3), 1996, pp. 319-331
Adenovirus-based vectors are promising candidates for genetic therapy
of cystic fibrosis (CF). Because adenoviruses naturally infect airway
cells, they grow to very high titers, and the transgenes carried by th
e adenoviruses are expressed at high levels. In addition, adenoviruses
are relatively safe because the disease caused by the wild-type virus
is self-limiting. One disadvantage of adenovirual vectors is that the
transgene expression would be transient because adenoviruses do not i
ntegrate their DNA into the genome of the host cells. Adenoviral gene
delivery into the lungs is also complicated by the anatomy of the airw
ays and the defense mechanisms of the recipient. To assess the feasibi
lity of adenovirus-mediated gene therapy for CF, a recombinant adenovi
rus carrying a lacZ gene was delivered into animal lungs to study the
efficiency and cellular distribution of gene transfer, the duration of
gene expression, the possible histopathology of the lungs after gene
transfer, and the efficacy of repeated administrations of the viral ag
ent. The results of these studies demonstrate that (i) efficient gene
transfer into animal lungs can be achieved; (ii) a near-homogenous del
ivery of the vectors can be achieved by airway instillation, although
the pattern of transduction varies among individual animals; (iii) pat
hological effects are generally mild in CD1 mice; (iv) gene expression
is transient; (v) repetitive gene transfer is achievable, but becomes
progressively less efficient, and (vi) immune responses are induced a
gainst both the viral and transgene products.