Copyright © 2003 by the European Society of Cardiology.
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Optimization of ultrasound-mediated gene transfer: comparison of contrast agents and ultrasound modalities1
a Division of Cardiovascular Diseases, Department of Biochemistry and Molecular Biology, Molecular Medicine Program, Mayo Clinic and Foundation, Rochester, MN, USA
b Basic Ultrasound Research Laboratory, Mayo Clinic and Foundation, Rochester, MN, USA
* Corresponding author. Robert D. Simari, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: 507-284-3727; fax: 507-284-8566
E-mail address: simari.robert{at}mayo.edu
Received 8 November 2002; revised 13 May 2003; accepted 27 July 2003
Aims Ultrasound (US)-enhanced gene transfer for cardiovascular disease is an emerging technique with translational relevance. Prior to pre-clinical applications, optimization of gene transfer using various US contrast agents and parameters is required. In order to do so, two clinically relevant contrast agents (Optison and PESDA), and two US modalities (dedicated continuous wave system and diagnostic scanner) were tested in vitro and in vivo.
Methods and Results In vitro, luciferase activity was measured after exposure of primary vascular cells to combinations of luciferase plasmid, contrast agents, and US exposures. US gene transfer was consistently superior to controls. PESDA was better than Optison; there was no significant difference between US modalities. In vivo, luciferase activity in skeletal muscle of rats was measured after injection of plasmid or adenovirus, expressing luciferase with or without US exposure. Diagnostic US was superior to continuous wave. US plasmid gene transfer was highly localized, and was superior to all controls except adenovirus which lacked spatial specificity. To deliver a secreted transgene product, US gene transfer of a plasmid expressing tissue factor pathway inhibitor (TFPI) to skeletal muscle resulted in a dose-related increase in plasma activity for up to 5 days after delivery.
Conclusion US-enhanced plasmid gene transfer is capable of transducing skeletal muscle in vivo either directly or via an intravascular route. This enhanced nonviral method is an alternative to plasmid DNA alone or viral vectors.
Key Words: Ultrasound • Gene transfer • Contrast agents
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