Cargando…

Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques

Systemically delivered adeno-associated viral (AAV) vectors are now in early-phase clinical trials for a variety of diseases. While there is a general consensus on inclusion and exclusion criteria for each of these trials, the conditions under which vectors are infused vary significantly. In this st...

Descripción completa

Detalles Bibliográficos
Autores principales: Greig, Jenny A, Nordin, Jayme ML, Bote, Erin, Makaron, Leah, Garnett, Mason E, Kattenhorn, Lisa M, Bell, Peter, Goode, Tamara, Wilson, James M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142508/
https://www.ncbi.nlm.nih.gov/pubmed/27933307
http://dx.doi.org/10.1038/mtm.2016.79
_version_ 1782472788313899008
author Greig, Jenny A
Nordin, Jayme ML
Bote, Erin
Makaron, Leah
Garnett, Mason E
Kattenhorn, Lisa M
Bell, Peter
Goode, Tamara
Wilson, James M
author_facet Greig, Jenny A
Nordin, Jayme ML
Bote, Erin
Makaron, Leah
Garnett, Mason E
Kattenhorn, Lisa M
Bell, Peter
Goode, Tamara
Wilson, James M
author_sort Greig, Jenny A
collection PubMed
description Systemically delivered adeno-associated viral (AAV) vectors are now in early-phase clinical trials for a variety of diseases. While there is a general consensus on inclusion and exclusion criteria for each of these trials, the conditions under which vectors are infused vary significantly. In this study, we evaluated the impact of intravenous infusion rate of AAV8 vector in cynomolgus macaques on transgene expression, vector clearance from the circulation, and potential activation of the innate immune system. The dose of AAV8 vector in terms of genome copies per kilogram body weight and its concentration were fixed, while the rate of infusion varied to deliver the entire dose over different time periods, including 1, 10, or 90 minutes. Analyses during the in-life phase of the experiment included sequential evaluation of whole blood for vector genomes and appearance of proinflammatory cytokines. Liver tissues were analyzed at the time of necropsy for enhanced green fluorescent protein (eGFP) expression and vector genomes. The data were remarkable with a relative absence of any statistically significant effect of infusion time on vector transduction, safety, and clearance. However, some interesting and unexpected trends did emerge.
format Online
Article
Text
id pubmed-5142508
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-51425082016-12-08 Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques Greig, Jenny A Nordin, Jayme ML Bote, Erin Makaron, Leah Garnett, Mason E Kattenhorn, Lisa M Bell, Peter Goode, Tamara Wilson, James M Mol Ther Methods Clin Dev Article Systemically delivered adeno-associated viral (AAV) vectors are now in early-phase clinical trials for a variety of diseases. While there is a general consensus on inclusion and exclusion criteria for each of these trials, the conditions under which vectors are infused vary significantly. In this study, we evaluated the impact of intravenous infusion rate of AAV8 vector in cynomolgus macaques on transgene expression, vector clearance from the circulation, and potential activation of the innate immune system. The dose of AAV8 vector in terms of genome copies per kilogram body weight and its concentration were fixed, while the rate of infusion varied to deliver the entire dose over different time periods, including 1, 10, or 90 minutes. Analyses during the in-life phase of the experiment included sequential evaluation of whole blood for vector genomes and appearance of proinflammatory cytokines. Liver tissues were analyzed at the time of necropsy for enhanced green fluorescent protein (eGFP) expression and vector genomes. The data were remarkable with a relative absence of any statistically significant effect of infusion time on vector transduction, safety, and clearance. However, some interesting and unexpected trends did emerge. Nature Publishing Group 2016-12-07 /pmc/articles/PMC5142508/ /pubmed/27933307 http://dx.doi.org/10.1038/mtm.2016.79 Text en Copyright © 2016 Official journal of the American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Article
Greig, Jenny A
Nordin, Jayme ML
Bote, Erin
Makaron, Leah
Garnett, Mason E
Kattenhorn, Lisa M
Bell, Peter
Goode, Tamara
Wilson, James M
Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques
title Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques
title_full Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques
title_fullStr Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques
title_full_unstemmed Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques
title_short Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques
title_sort impact of intravenous infusion time on aav8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142508/
https://www.ncbi.nlm.nih.gov/pubmed/27933307
http://dx.doi.org/10.1038/mtm.2016.79
work_keys_str_mv AT greigjennya impactofintravenousinfusiontimeonaav8vectorpharmacokineticssafetyandlivertransductionincynomolgusmacaques
AT nordinjaymeml impactofintravenousinfusiontimeonaav8vectorpharmacokineticssafetyandlivertransductionincynomolgusmacaques
AT boteerin impactofintravenousinfusiontimeonaav8vectorpharmacokineticssafetyandlivertransductionincynomolgusmacaques
AT makaronleah impactofintravenousinfusiontimeonaav8vectorpharmacokineticssafetyandlivertransductionincynomolgusmacaques
AT garnettmasone impactofintravenousinfusiontimeonaav8vectorpharmacokineticssafetyandlivertransductionincynomolgusmacaques
AT kattenhornlisam impactofintravenousinfusiontimeonaav8vectorpharmacokineticssafetyandlivertransductionincynomolgusmacaques
AT bellpeter impactofintravenousinfusiontimeonaav8vectorpharmacokineticssafetyandlivertransductionincynomolgusmacaques
AT goodetamara impactofintravenousinfusiontimeonaav8vectorpharmacokineticssafetyandlivertransductionincynomolgusmacaques
AT wilsonjamesm impactofintravenousinfusiontimeonaav8vectorpharmacokineticssafetyandlivertransductionincynomolgusmacaques