83. Adenoviral Mediated Compartmentalized Liver Transduction Improves Safety and Yields Long-term Transgene Expression in a Porcine Model

Abstract

To stringently control the viremia associated with conventional routes of vector administration and significantly reduce the astronomical quantities of virus commonly infused in gene therapy, our group described compartmentalized liver transduction. Compartmentalized liver transduction is based on known adenoviral spatio-temporal kinetics and is achieved by the intra-parenchymal injection of a vector dose into a blood flow isolated portion of the liver; perfusion is reestablished after viral endocytosis has been completed (30 min). Given the encouraging results documented in rodents (rats), our group assessed compartmentalized liver transduction in a porcine model. To this end, a surgical device was conceptualized, prototyped and utilized to safely and securely transiently isolate a portion of the liver in 25- 30 kg Vietnamese pigs. Implementing compartmentalized liver transduction in pigs, no viremia was detected during the procedure and transgene expression and presence were confined to the site of vector injection. Neither inflammation, apoptosis or significant biochemical liver damage were observed. Using porcine alpha fetoprotein as a reporter gene, serum levels were documented with low quantities of vector dose (10^5) and prolonged transgene expression was achieved (10 months). Our results further support that compartmetalized liver transduction has profound paradoxic effects on the classic toxicological interactions between the liver and adenovirus. The lack of acute liver inflammation observed suggests that conventional immunolgical thresholds and relays were not triggered. We further postulate that compartmentalized liver transduction induces the local synthesis of tolerance inducing cytokines central to thwarting the acute, intermediate and late adenoviral induced immune responses and are critical in generating an immune priviledge liver compartment capable of long term protein synthesis and secretion. Our results further demonstrate that compartmentalized liver transduction is a safe and effective route of vector delivery with a promising future in the field of gene therapy.