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Gene delivery to the spinal cord using MRI-guided focused ultrasound

Gene Therapy volume 22, pages 568–577 (2015)Cite this article

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Abstract

Non-invasive gene delivery across the blood–spinal cord barrier (BSCB) remains a challenge for treatment of spinal cord injury and disease. Here, we demonstrate the use of magnetic resonance image-guided focused ultrasound (MRIgFUS) to mediate non-surgical gene delivery to the spinal cord using self-complementary adeno-associated virus serotype 9 (scAAV9). scAAV9 encoding green fluorescent protein (GFP) was injected intravenously in rats at three dosages: 4 × 108, 2 × 109 and 7 × 109 vector genomes per gram (VG g−1). MRIgFUS allowed for transient, targeted permeabilization of the BSCB through the interaction of focused ultrasound (FUS) with systemically injected Definity lipid-shelled microbubbles. Viral delivery at 2 × 109 and 7 × 109 VG g−1 leads to robust GFP expression in FUS-targeted regions of the spinal cord. At a dose of 2 × 109 VG g−1, GFP expression was found in 36% of oligodendrocytes, and in 87% of neurons in FUS-treated areas. FUS applications to the spinal cord could address a long-term goal of gene therapy: delivering vectors from the circulation to diseased areas in a non-invasive manner.

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Acknowledgements

This work was supported by the Centre for Spinal Trauma, Sunnybrook Health Sciences Centre, CIHR FRN 93603 (IA), NIH grant R01-EB003268 (KH) and the Canada Research Chair Program (KH). We thank Dr Paul Nagy for helping to edit this manuscript. We also thank Dr Julie Korich and MBF Bioscience for their counsel in regard to cell counting.

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Authors and Affiliations

  1. Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada

    D Weber-Adrian, E Thévenot, K Markham-Coultes & I Aubert

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    D Weber-Adrian, E Thévenot & I Aubert

  3. Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada

    M A O'Reilly, W Oakden, N Ellens, A Burgess, A J M Yee, C M Whyne, G J Stanisz & K Hynynen

  4. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    W Oakden, N Ellens, G J Stanisz & K Hynynen

  5. TECHNA Institute, University Health Network, Toronto, Ontario, Canada

    M K Akens

  6. Department of Surgery, University of Toronto, Toronto, Ontario, Canada

    M K Akens, J Finkelstein, A J M Yee & C M Whyne

  7. Division of Orthopaedic Surgery, Centre for Spinal Trauma, Sunnybrook Research Institute, Toronto, Ontario, Canada

    J Finkelstein, A J M Yee & C M Whyne

  8. Department of Neuroscience, Ohio State University and Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA

    K D Foust & B K Kaspar

  9. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    R Chopra

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  1. D Weber-Adrian
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Correspondence to I Aubert.

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Weber-Adrian, D., Thévenot, E., O'Reilly, M. et al. Gene delivery to the spinal cord using MRI-guided focused ultrasound. Gene Ther 22, 568–577 (2015). https://doi.org/10.1038/gt.2015.25

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