651. VRX-007, an Oncolytic Adenovirus Vector, Replicates in Syrian Hamsters but Not Mice: Comparison of Biodistribution Studies Performed in the Syrian Hamster and Mouse
Authors: Drew L. Lichtenstein, Karoly Toth, Jaqueline F. Spencer, Jenifer Meyer, Baoling Ying, Ann E. Tollefson, Debabrata Patra, Elena Shashkova, Mohan Kuppuswamy, Konstantin Doronin, Debanjan Dhar, Louis A. Zumstein, William S.M. Wold
Journal: Molecular Therapy (2006)

Two biodistribution studies, one in Syrian golden hamsters (Mesocricetus auratus) and one in C57BL/6 mice, were performed to examine the dissemination and pharmacokinetics of VRX-007, a replication-competent (oncolytic) adenovirus (Ad) vector, following intravenous administration. The study in Syrian hamsters allowed us to examine the biodistribution of VRX-007 in a model that is permissive for VRX-007 (and Ad5) replication. In contrast, mice do not support replication of human Ads to an appreciable extent. Controls in the Syrian hamster study included wild-type Ad5 (replication-competent virus), AdCMVpA (a replication-defective vector), and vehicle only. Two quantitative real-time polymerase chain reaction (QPCR) assays were developed, one that specifically and exclusively detects VRX-007 vector genomic DNA (gDNA) and another that specifically detects both Ad5 and AdCMVpA gDNA. These assays were used to detect viral gDNA present in blood and various organs collected from Syrian hamsters (VRX-007 and Ad5/AdCMVpA assays) or C57BL/6 mice (VRX-007 assay only). In addition, the level of infectious virus/vector present in select Syrian hamster organs was titrated using a tissue culture infectious dose-50 (TCID50) assay. Both studies demonstrate that early after administration the virus/vector is distributed widely. In the Syrian hamster study, gDNA from the replication-competent vector/virus VRX-007 and Ad5 was more abundant than that of the replication-defective vector AdCMVpA on Days 2 and 7. On Days 29 and 92, the levels of VRX-007, Ad5, and AdCMVpA Gdna were roughly the same. In addition, there was an increase in VRX-007 and Ad5 copy number from Day 2 to Day 7 in heart, kidney, and adrenal glands (VRX-007 only) that was not seen with AdCMVpA. Infectious vector/virus was recovered from the livers, lungs, and testes of VRX-007- and Ad5-injected hamsters (Days 2 and 7 only), but not from any organs of AdCMVpA-injected hamsters. There was no detectable infectious virus on Day 29 or Day 92. The data in Syrian hamsters contrasts with that obtained in mice, where VRX-007 copy number was generally low on Day 2 (except in the liver), and in many organs decreased to undetectable levels over time. In addition, no infectious VRX-007 was recovered from mouse livers. From these studies we: 1) confirm and extend observations that Syrian hamsters are permissive for Ad replication, which occurred in the liver, lungs, and possibly other organs, 2) confirm that Ad does not replicate to an appreciable extent in C57BL/6 mice, 3) show that the liver is the primary organ of infection in Syrian hamsters and mice when virus/vector is delivered intravenously. The results of these studies will be discussed in light of data obtained from parallel toxicology studies in these two animal species.