Conclusions
In this study, the author first demonstrated that it was feasible to normalize dose response relationship of AAV-mediated hemophilia GT in multiple species to a species-invariant scale. The normalized dose response relationship from preclinical species could be extrapolated to hemophilia patients and used to predict FIH dose of AAV vectors for hemophilia therapy. In addition to hemophilia dogs and non-human primates, inclusion of larger animal models (e.g., swine and cattle) in preclinical dose-finding studies of AAV vectors is expected to improve the performance of interspecies dose-response normalization approach. Furthermore, AAV capsid-specific T cell responses in hemophilia patients may cause underprediction of FIH dose by the interspecies dose-response normalization approach. On the other hand, novel bioengineered capsids with a high transduction efficiency specifically in human hepatocytes may cause overprediction of FIH dose. Prior to a FIH study, in vitro tests should be used to detect AAV vector candidates with a high risk of AAV capsid-specific T cell responses and humanized animal liver models can be used to detect AAV vector candidates with a large interspecies difference in hepatocyte transduction. These interspecies differences in immune responses and vector transduction efficiency should be considered when dose response is extrapolated from preclinical species to patients.