Transgene Expression in Dogs after Liver-Directed Hydrodynamic Delivery of Sleeping Beauty Transposons Using Balloon Catheters

Kendra A. Hyland, Elena L. Aronovich, Erik R. Olson, Jason B. Bell, Myra Urness Rusten, Roland Gunther, David W. Hunter, Perry B. Hackett, R. Scott Mcivor

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The Sleeping Beauty transposon system has been extensively tested for integration of reporter and therapeutic genes in vitro and in vivo in mice. Dogs were used as a large animal model for human therapy and minimally invasive infusion of DNA solutions. DNA solutions were delivered into the entire liver or the left side of the liver using balloon catheters for temporary occlusion of venous outflow. A peak intravascular pressure between 80 and 140 mmHg supported sufficient DNA delivery in dog liver for detection of secretable reporter proteins. Secretable reporters allowed monitoring of the time course of gene products detectable in the circulation postinfusion. Canine secreted alkaline phosphatase reporter protein levels were measured in plasma, with expression detectable for up to 6 weeks, while expression of canine erythropoietin was detectable for 7-10 days. All animals exhibited a transient increase in blood transaminases that normalized within 10 days; otherwise the treated animals were clinically normal. These results demonstrate the utility of a secreted reporter protein for real-time monitoring of gene expression in the liver in a large animal model but highlight the need for improved delivery in target tissues to support integration and long-term expression of Sleeping Beauty transposons.

Original languageEnglish (US)
Pages (from-to)541-550
Number of pages10
JournalHuman gene therapy
Volume28
Issue number7
DOIs
StatePublished - Jul 2017

Bibliographical note

Publisher Copyright:
© 2017, Mary Ann Liebert, Inc.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • Hydrodynamic
  • Sleeping Beauty
  • canine
  • liver
  • non-viral
  • transposon

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