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Focused ultrasound (HIFU) induces localized enhancement of reporter gene expression in rabbit carotid artery

Gene Therapy volume 10, pages 1600–1607 (2003)Cite this article

Abstract

The development of accurate, safe, and efficient gene delivery remains a major challenge towards the realization of gene therapeutic prevention and treatment of cardiovascular diseases. In this study, we investigated the ability of high-intensity focused ultrasound (HIFU), a form of mechanical wave transmission, to act as a noninvasive tool for the enhancement of in vivo gene transfer into rabbit carotid arteries. Segments of the common carotid arteries of New Zealand white rabbits were isolated and infused with plasmid DNA encoding the reporter β-galactosidase either with or without the addition of ultrasound contrast agent consisting of small (∼2–5 μm) gas-filled human albumin microspheres to augment cavitation. Infused arteries were exposed to pulsed ultrasound for 1 min (frequency 0.85 MHz, burst length 50 ms, repetition frequency 1 Hz, duration 60 s, peak pressure amplitude of 15 MPa). At 6.3 MPa, HIFU enhanced gene expression eight-fold, and 17.5-fold in the presence of contrast. We found increasing amounts of β-galactosidase expression in the carotid vessel with increasing pressure amplitude. This dose–response relation was present with and without contrast. Without contrast, no vessel damage was detected up to 15 MPa, while the addition of contrast induced side effects above a threshold of 6.3 MPa peak pressure. The entire procedure was feasible and safe for the animals, and the results suggest that HIFU has the potential to assist in the noninvasive spatial regulation of gene transfer into the vascular system.

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Acknowledgements

This research was supported by NCI Grant CA 46627, NHLBI Grants HL35610 and HL58516 and a Grant from the Deutsche Forschungsgemeinschaft (DFG Hu 798/1-1). MJM was supported by the William Randolph Hearst Endowment for Young Investigators. VJD is the recipient of an NHLBI MERIT Award.

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Authors and Affiliations

  1. Department of Radiology, Brigham and Womens' Hospital, Harvard Medical School, Boston, MA, USA

    P E Huber, F Jolesz & K Hynynen

  2. Department of Medicine, Brigham and Womens' Hospital, Harvard Medical School, Boston, MA, USA

    M J Mann, L G Melo, A Ehsan, D Kong, L Zhang, M Rezvani & V J Dzau

  3. Department of Radiation Oncology, German Cancer Research Center (dkfz), Heidelberg, Germany

    P E Huber & P Peschke

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  1. P E Huber
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Huber, P., Mann, M., Melo, L. et al. Focused ultrasound (HIFU) induces localized enhancement of reporter gene expression in rabbit carotid artery. Gene Ther 10, 1600–1607 (2003). https://doi.org/10.1038/sj.gt.3302045

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