Abstract
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.
Original language | American English |
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Pages (from-to) | 368-379 |
Number of pages | 12 |
Journal | Molecular Therapy - Methods and Clinical Development |
Volume | 27 |
DOIs | |
State | Published - Dec 8 2022 |
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
Keywords
- AAV gene therapy
- in vivo model
- model informed drug dosing
- pharmacokinetics
- predictive dosing