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

JA Greig, JML Nordin, E Bote, L Makaron… - … Therapy Methods & …, 2016 - cell.com
JA Greig, JML Nordin, E Bote, L Makaron, ME Garnett, LM Kattenhorn, P Bell, T Goode…
Molecular Therapy Methods & Clinical Development, 2016cell.com
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 …
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.
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