Allometric-like scaling of AAV gene therapy for systemic protein delivery

The use of adeno-associated virus (AAV) as a gene delivery vehicle for secreted peptide therapeutics can enable a new approach to durably manage chronic protein insufficiencies in patients. Yet, dosing of AAVs have been largely empirical to date. In this report, we explore the dose-response relationship of AAVs encoding a secreted luciferase reporter to establish a mathematical model that can be used to predict steady-state protein concentrations in mice based on steady-state secretion rates in vitro. Upon intravenous administration of AAV doses that scaled multiple logs, steady-state plasma concentrations of a secreted reporter protein were fit with a hyperbolic dose-response equation. Parameters for the hyperbolic model were extracted from the data and compared with create scaling factors that related in vitro protein secretion rates to in vivo steady-state plasma concentrations. Parathyroid hormone expressed by AAV was then used as a bioactive candidate and validated that the model, with scaling factors, could predict the plasma hormone concentrations in mice. In total, this model system confirmed that plasma steady-state concentrations of secreted proteins expressed by AAVs can be guided by in vitro kinetic secretion data laying groundwork for future customization and model-informed dose justification for AAV candidates.