SYSTEMATIC ANALYSIS OF REPEATED GENE DELIVERY INTO ANIMAL LUNGS WITH A RECOMBINANT ADENOVIRUS VECTOR

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.