Ovine adenovirus vectors overcome preexisting humoral immunity against human adenoviruses in vivo.
Recombinant human adenoviruses (hAd) have become widely used as tools to achieve efficient gene transfer. However, successful application of hAd-derived vectors in clinical trials is limited due to immunological and potential safety problems inherent in their human origin. In this study, we describe a recombinant ovine adenovirus (OAV) as an alternative vector for gene transfer in vivo. In contrast to an hAd vector, the OAV vector was not neutralized by human sera. An OAV vector which contained the cDNA of the human alpha1-antitrypsin (hAAT) gene linked to the Rous sarcoma virus promoter was generated and administered systemically to mice. The level and duration of hAAT gene expression was similar to that achieved with an hAd counterpart in both immunocompetent and immunodeficient mice. However, the tissue distribution of the OAV vector differed from that observed for hAd vectors in that the liver was not the dominant target. Significantly, we demonstrated efficient gene transfer with the OAV vector into mice immunized with hAd vectors and vice versa. We also confirm that the immune response to a transgene product can prevent its functional expression following sequential application of a vector. Our results suggest a possible solution to endemic humoral immunity against currently used hAd vectors and should therefore have an impact on the design of improved gene therapy protocols utilizing adenovirus vectors.
Hofmann
C
C
HepaVec AG für Gentherapie, 13122 Berlin-Buch, Germany. chofmann@hepavec.com
Löser
P
P
Cichon
G
G
Arnold
W
W
Both
G W
GW
Strauss
M
M
D000260:Adenoviruses, Human / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D000917:Antibody Formation; D002460:Cell Line; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D017921:Mastadenovirus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009500:Neutralization Tests; D011995:Recombination, Genetic; D012756:Sheep; D014018:Tissue Distribution; D000515:alpha 1-Antitrypsin / Q000235:genetics*
D000914:Antibodies, Viral; D000515:alpha 1-Antitrypsin