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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 relation...

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Autores principales: Burr, Alexandra, Erickson, Patrick, Bento, Raphaela, Shama, Kariman, Roth, Charles, Parekkadan, Biju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9641010/
https://www.ncbi.nlm.nih.gov/pubmed/36381306
http://dx.doi.org/10.1016/j.omtm.2022.10.011
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author Burr, Alexandra
Erickson, Patrick
Bento, Raphaela
Shama, Kariman
Roth, Charles
Parekkadan, Biju
author_facet Burr, Alexandra
Erickson, Patrick
Bento, Raphaela
Shama, Kariman
Roth, Charles
Parekkadan, Biju
author_sort Burr, Alexandra
collection PubMed
description 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.
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spelling pubmed-96410102022-11-14 Allometric-like scaling of AAV gene therapy for systemic protein delivery Burr, Alexandra Erickson, Patrick Bento, Raphaela Shama, Kariman Roth, Charles Parekkadan, Biju Mol Ther Methods Clin Dev Original Article 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. American Society of Gene & Cell Therapy 2022-10-21 /pmc/articles/PMC9641010/ /pubmed/36381306 http://dx.doi.org/10.1016/j.omtm.2022.10.011 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Burr, Alexandra
Erickson, Patrick
Bento, Raphaela
Shama, Kariman
Roth, Charles
Parekkadan, Biju
Allometric-like scaling of AAV gene therapy for systemic protein delivery
title Allometric-like scaling of AAV gene therapy for systemic protein delivery
title_full Allometric-like scaling of AAV gene therapy for systemic protein delivery
title_fullStr Allometric-like scaling of AAV gene therapy for systemic protein delivery
title_full_unstemmed Allometric-like scaling of AAV gene therapy for systemic protein delivery
title_short Allometric-like scaling of AAV gene therapy for systemic protein delivery
title_sort allometric-like scaling of aav gene therapy for systemic protein delivery
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9641010/
https://www.ncbi.nlm.nih.gov/pubmed/36381306
http://dx.doi.org/10.1016/j.omtm.2022.10.011
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