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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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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 |
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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 |
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