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.