title: Impact of intravenous infusion time on AAV8 vector pharmacokinetics, safety, and liver transduction in cynomolgus macaques.
abstract: 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.
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Greig
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Jayme Ml
authors.initials: JM
authors.lastname: Nordin
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Bote
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Makaron
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Mason E
authors.initials: ME
authors.lastname: Garnett
authors.affiliation: Dimension Therapeutics , Cambridge, Massachusetts, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kattenhorn
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Bell
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Goode
authors.affiliation: Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson