223. Duration of Factor IX Expression in Macaques Following AAV8-Mediated Liver Transduction

Abstract

We have been evaluating the efficacy and safety of hemophilia gene therapy using macaques, and demonstrated that liver-targeted approach with AAV8-based vector has resulted in therapeutic level of factor IX expression at the practical vector doses. Another important finding is the inhibitory effect of neutralizing antibody (NAb) against AAV capsid upon AAV vector-based gene transfer approach; none of the subjects with positive NAb showed recognizable transgene expression following IV injection of the vector. At this stage, one of the most crucial questions is the duration of this therapeutic modality. As this approach utilizes hepatocyte transduction by a non-integrating vector, the length of this therapy should depend on the lifetime of the transduced cells. During the series of experiment, we observed 5 animals for long-term outcome (longer than 3 years). All of these animals showed therapeutic levels of factor IX expression following vector injection, and the expression levels lasted throughout the observation period in all of the animals. In one animal, the expression level was kept constant within therapeutic level for more than 7 years. No adverse effect was observed in any of the animals. These findings suggest long-term efficacy and safety of this therapeutic approach, supporting application to human treatment. This study was performed in collaboration with Tsukuba Primate Research Center, National Institute for Biomedical Innovation, and The Corporation for Production and Research of Laboratory Primates, Japan.