First-in-Patient Dose Prediction for Adeno-Associated Virus-Mediated Hemophilia Gene Therapy Using Allometric Scaling.

In this study, the author compared the performance of two allometric scaling approaches and body-weight-based dose conversion approach for first-in-patient (FIP) dose prediction for adeno-associated virus (AAV)-mediated hemophilia gene therapy using preclinical and clinical efficacy data of nine AAV vectors. In general, body-weight-based direct conversion of effective doses in monkeys or dogs was more likely to underestimate FIP dose but worked for one bioengineered vector with a high transduction efficiency specifically in humans. In contrast, allometric scaling between gene efficiency factor (log GEF) and body weight (log W ) was likely to overestimate FIP dose but worked for two vectors with capsid-specific T-cell responses in patients. The third approach, allometric scaling between log GEF and W -0.25 was appropriate for FIP dose prediction in the absence of T-cell responses to AAV vectors or a dramatic difference in vector transduction efficiency between animals and humans.