SERO-SWITCH ADENOVIRUS-MEDIATED IN-VIVO GENE-TRANSFER - CIRCUMVENTIONOF ANTI-ADENOVIRUS HUMORAL IMMUNE DEFENSES AGAINST REPEAT ADENOVIRUS VECTOR ADMINISTRATION BY CHANGING THE ADENOVIRUS SEROTYPE

Recombinant, replication-deficient adenovirus (Ad) vectors have been s uccessfully used to transfer and express the normal human cystic fibro sis transmembrane conductance regulator (CFTR) cDNA in vivo in the res piratory epithelium of experimental animals and humans with cystic fib rosis (CF). Since Ad-directed gene expression wanes over time, repeat administration is necessary to achieve an effective treatment for CF. A major hurdle to such a strategy is the possibility that anti-Ad humo ral immunity may prevent gene expression in individuals with pre-exist ing anti-Ad immunity or following repeat administration. One strategy to circumvent such a problem would be alternating the use of Ad vector s belonging to different subgroups. Neutralizing antibodies developed with the administration of one Ad serotype do not cross-react with an Ad belonging to a second serotype in a manner that blocks infection an d gene expression. To test this hypothesis, an immunizing dose of wild -type Ad5 (subgroup C), Add (subgroup E), or Ad30 (subgroup D) was adm inistered intratracheally to experimental animals, followed by an intr atracheal administration of a replication-deficient subgroup C-derived vector coding for marker genes (chloramphenicol acetyl transferase or beta-galactosidase) or for the normal human CFTR cDNA. As expected, s tudies with vectors coding for marker genes or for CFTR cDNA demonstra ted that airway administration of a vector does not yield efficient ge ne transfer, if there has been prior recent airway administration of t he same Ad subgroup. In contrast, effective expression from the second administration can be achieved with an adenovirus vector belonging to a subgroup different from the first adenovirus administered. These da ta support the paradigm of alternating Ad vectors derived from differe nt subgroups as strategy to circumvent anti-Ad humoral immunity, thus permitting the use of Ad vectors as a means to treat the respiratory m anifestations of CF.