Local delivery of a viral vector mitigates neutralization by antiviral antibodies and results in efficient transduction of rabbit liver.
Antiviral antibodies within the human population remain a barrier to the effective clinical use of viral gene transfer vectors. We have asked whether local, balloon catheter-mediated delivery of a viral vector to the rabbit liver using a hepatic vein might mitigate the neutralizing effects of antiviral antibodies. We have compared directly the ability of adenovirus (Ad2) encoding nuclear-localized beta-galactosidase to infect the rabbit liver after local and systemic delivery in both the presence and the absence of defined anti-Ad2 antibody titers. In naive rabbits, local delivery resulted in higher beta-galactosidase expression compared to systemic delivery. In the presence of passively administered anti-Ad2 antibodies, local delivery resulted in expression levels that were comparable to those obtained in naive rabbits by systemic delivery. Local delivery also resulted in the majority of expression originating from hepatocytes, even in passively immunized animals, a result that could not be duplicated using the systemic approach. Since systemic delivery of adenovirus in naive animal models results in transgene expression levels often regarded as therapeutic, these results predict that local hepatic vein delivery of a viral vector is a clinically practical approach to mitigate neutralizing antiviral antibodies and generate therapeutic levels of transgene expression.
Hodges
Bradley L
BL
Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701, USA.
Taylor
Kristin M
KM
Chu
Qiuming
Q
Scull
Samantha E
SE
Serriello
Rebecca G
RG
Anderson
Scott C
SC
Wang
Fei
F
Scheule
Ronald K
RK
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003627:Data Interpretation, Statistical; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008297:Male; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry; D019076:Transgenes; D001616:beta-Galactosidase / Q000378:metabolism
D011994:Recombinant Proteins; D001616:beta-Galactosidase