531. Balloon Catheter-Mediated Hepatic Vein Delivery of a Viral Vector Mitigates Neutralization by Anti-Viral Antibodies and Results in Efficient Transduction of Rabbit Liver

Abstract

The liver, and in particular, hepatocytes, represent an attractive target for both viral and non-viral gene transfer vectors. However, there are certain delivery issues associated with both of these vector systems that make their use in humans problematic. In particular, for viral vectors, the existence of anti-viral antibodies in the general population represents a potential barrier to their effective use in the clinic. Building upon our earlier success using balloon catheters to deliver plasmid DNA by way of the hepatic venous circulation to rabbit liver, we have used this same model to ask if we could use a similar approach to deliver a model viral vector. Specifically, we have compared a local, balloon catheter-mediated hepatic vein delivery protocol to systemic delivery of a CMV-driven adenoviral vector expressing b-galactosidase in terms of liver transduction efficiency, toxicity, and cell types transduced. We have also made this comparison in the presence of defined anti-AdV antibody titers in the recipient rabbits. In the naive animal, local balloon catheter-based delivery conferred an advantage in overall liver transduction when compared to systemic delivery of an identical dose of virus. In rabbits bearing anti-AdV antibody titers equivalent to those found in pooled human serum, this difference in expression between local and systemic delivery was even more striking. Importantly, in the presence of passively-administered anti-AdV antibodies, balloon-catheter mediated delivery resulted in expression levels that were comparable to those obtained by systemic delivery of an equivalent dose in a naive animal. Since in general, systemic delivery of AdV in naive animal models results in expression levels of secreted proteins regarded as therapeutic, the present results predict that retrograde delivery by a hepatic vein route using a balloon catheter should result in therapeutic levels of expression, even in the presence of average human levels of anti-AdV antibodies. Further support for this hypothesis is the finding that this local hepatic vein delivery approach resulted in the majority of expression originating from hepatocytes even in the passively immunized animals. In contrast, systemic delivery of AdV in passively immunized animals resulted in the majority of expression originating from non-hepatocytes. This latter finding implies that this local approach should help minimize the transduction of antigen-presenting cells, thereby reducing any immune consequences of viral transduction. Taken together, these data suggest that coupled with additional features such as a hepatocyte-specific expression cassette, balloon catheter viral-mediated transduction of the liver may represent a practical clinical approach for treating indications for which hepatocytes can be used as a depot for therapeutic protein production.