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Methods Mol Biol. 2019;1950:177-197. doi: 10.1007/978-1-4939-9139-6_10.

MRI-Guided Focused Ultrasound for Targeted Delivery of rAAV to the Brain.

Author information

1
Brain Sciences, Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.
2
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
3
Physical Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.
4
AveXis, San Diego, CA, USA.
5
Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.
6
Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
7
Brain Sciences, Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada. isabelle.aubert@sri.utoronto.ca.
8
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. isabelle.aubert@sri.utoronto.ca.

Abstract

Recombinant adeno-associated viral (rAAV) vectors are a promising tool for therapeutic gene delivery to the brain. However, the delivery of rAAVs across the blood-brain barrier (BBB) and entry into the brain remains a major challenge for rAAV-based gene therapy. To circumvent this limitation, transcranial MRI-guided focused ultrasound (MRIgFUS) combined with intravenously injected microbubbles has been used to transiently and reversibly increase BBB permeability in targeted brain regions. Systemic administration of rAAVs at the time of sonication with focused ultrasound (FUS) facilitates the passage of rAAVs through the BBB and into the brain parenchyma. We and others have demonstrated that FUS-mediated rAAV delivery to the brain results in efficient transduction and transgene expression in vivo. Using this approach, the dose of intravenously injected rAAV variants that can cross the BBB can be reduced by 100 times, achieving significant transgene expression in the brain parenchyma with reduced peripheral transduction. Moreover, this strategy can be used to deliver rAAV variants that do not cross the BBB from the blood to selected brain regions. Here, we provide a detailed protocol for FUS-induced BBB permeability for targeted rAAV delivery to the brain of adult mice and rats.

KEYWORDS:

Adeno-associated virus; Blood-brain barrier; Focused ultrasound; Gene therapy; Viral vector delivery

PMID:
30783974
PMCID:
PMC6546162
DOI:
10.1007/978-1-4939-9139-6_10
[Indexed for MEDLINE]
Free PMC Article

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