title: Gene delivery to the spinal cord using MRI-guided focused ultrasound.
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 × 10(8), 2 × 10(9) and 7 × 10(9) 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 × 10(9) and 7 × 10(9) VG g(-1) leads to robust GFP expression in FUS-targeted regions of the spinal cord. At a dose of 2 × 10(9) 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.
authors.affiliation: 1] Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Weber-Adrian
authors.affiliation: 1] Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Thévenot
authors.affiliation: Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: O'Reilly
authors.affiliation: 1] Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Oakden
authors.affiliation: 1] TECHNA Institute, University Health Network, Toronto, Ontario, Canada [2] Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: M K
authors.initials: MK
authors.lastname: Akens
authors.affiliation: 1] Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Ellens
authors.affiliation: Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Markham-Coultes
authors.affiliation: Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Burgess
authors.affiliation: 1] Department of Surgery, University of Toronto, Toronto, Ontario, Canada [2] Centre for Spinal Trauma, Division of Orthopaedic Surgery, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Finkelstein
authors.affiliation: 1] Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada [2] Department of Surgery, University of Toronto, Toronto, Ontario, Canada [3] Centre for Spinal Trauma, Division of Orthopaedic Surgery, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: A J M
authors.initials: AJ
authors.lastname: Yee
authors.affiliation: 1] Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada [2] Department of Surgery, University of Toronto, Toronto, Ontario, Canada [3] Centre for Spinal Trauma, Division of Orthopaedic Surgery, Sunnybrook Research Institute, Toronto, Ontario, Canada.
authors.forename: C M
authors.initials: CM
authors.lastname: Whyne
authors.affiliation: Department of Neuroscience, Ohio State University and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Foust
authors.affiliation: Department of Neuroscience, Ohio State University and Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Kaspar
authors.affiliation: 1] Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: G J
authors.initials: GJ
authors.lastname: Stanisz
authors.affiliation: Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Chopra
authors.affiliation: 1] Department of Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Hynynen
authors.affiliation: 1] Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: I
authors.initials: I
authors.lastname: Aubert
mesh_terms: D000818:Animals; D000229:Dependovirus; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000235:genetics* / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia; D017208:Rats, Wistar; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism*; D013118:Spinal Cord Diseases / Q000235:genetics / Q000628:therapy*; D014463:Ultrasonography / Q000379:methods
chemical_list: D049452:Green Fluorescent Proteins