The performances of 2 allometric scaling approaches—AS-log W and AS-W–0.25—and a body weight-based dose conversion approach for first-in-patient (FIP) dose prediction for adeno-associated virus (AAV)-mediated hemophilia gene therapy were compared by a researcher, using preclinical and clinical targeted protein expression data of vectors collected from published literature.

Only vectors with clinical data and preclinical data from 2 or more species were obtained. Results of the analysis were published recently in Molecular Pharmaceutics.

Hemophilia is an inherited bleeding disorder, and it was one of the earliest diseases to be considered for gene therapy. Hemophilia A and B, the most common types of the disorder, are caused by mutations in the F8 and F9 genes, coding for factor VIII (FVIII) and factor IX (FIX), respectively. FIP dose selection for gene therapy in patients with hemophilia should be based on the targeted plasma levels of FVIII and FIX. Mice, dogs, and monkeys are typically used as the animal models for AAV-mediated gene therapy.

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Five vectors for hemophilia A gene therapy and 6 vectors for hemophilia B gene therapy were identified. For AMT-061—a vector for hemophilia B gene therapy—only plasma FIX data from monkeys and humans were available. For SPK-9001—another vector for hemophilia B gene therapy—only plasma FIX data from humans were available. The gene efficiency factor (GEF) values of AMT-061 and SPK-9001 were computed, but allogenic scaling could not be performed. Therefore, data on 5 FVIII vectors and 4 FIX vectors were ultimately applied to allometric scaling analyses.

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Results of the study showed that body weight-based direct conversion of effective doses in monkeys and dogs was more likely to underestimate FIP dose; however, it worked for 1 bioengineered vector with a high human hepatocyte transduction efficiency.

In comparison, allometric scaling between GEF (log GEF) and body weight (log W) was likely to overestimate the FIP dose, but it worked for 2 vectors with capsid-specific T-cell responses in patients. The third approach—allometric scaling between log GEF and W–0.25—was relevant for FIP dose prediction in the absence of T-cell responses to AAV vectors or a striking difference in vector transduction efficiency between humans and animals.

Overall, 3 factors—body weight of preclinical species and patients, immune responses, and human-specific transduction efficiency—should be taken into account when predicting the FIP dose of AAV-mediated hemophilia gene therapy using preclinical data, the author wrote.

The author concluded that “Continuous collaborative research is warranted to apply the allometric scaling approach to gene replacement therapy products for other diseases and other viral and nonviral gene therapy modalities.”


Zou P. First-in-patient dose prediction for adeno-associated virus-mediated hemophilia gene therapy using allometric scaling. Mol Pharm. Published online November 14, 2022. doi:10.1021/acs.molpharmaceut.2c00555