Noninvasive and Targeted Gene Delivery into the Brain Using Microbubble-Facilitated Focused Ultrasound
Open accessAbstract
Recombinant adeno-associated viral (rAAV) vectors are potentially powerful tools for gene therapy of CNS diseases, but their penetration into brain parenchyma is severely limited by the blood-brain barrier (BBB) and current delivery relies on invasive stereotactic injection. Here we evaluate the local, targeted delivery of rAAV vectors into the brains of mice by noninvasive, reversible, microbubble-facilitated focused ultrasound (FUS), resulting in BBB opening that can be monitored and controlled by magnetic resonance imaging (MRI). Using this method, we found that IV-administered AAV2-GFP (green fluorescence protein) with a low viral vector titer (1×10(9) vg/g) can successfully penetrate the BBB-opened brain regions to express GFP. We show that MRI monitoring of BBB-opening could serve as an indicator of the scale and distribution of AAV transduction. Transduction peaked at 3 weeks and neurons and astrocytes were affected. This novel, noninvasive delivery approach could significantly broaden the application of AAV-viral-vector-based genes for treatment of CNS diseases.
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AAV1, AAV2, or chimeric AAV1/2 vectors, which showed low BBB-crossing per se, successfully penetrated into directed brain regions after FUS-MB treatment.
“It was reported that IV infusion of AAV1, AAV2 or chimeric AAV1/2 vector, which showed low BBB-crossing per se, successfully penetrated into directed brain regions after FUS-MB treatment [140–142].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [140]
The Abstract and Discussion report that intravenously administered AAV2 entered targeted, FUS-opened brain regions in mice, while the Introduction and Results describe poor delivery across an intact BBB. The paper does not report FUS-assisted brain delivery of AAV1 or chimeric AAV1/2 vectors, so it supports only the AAV2 portion of the sentence. (LLM, conf=0.86)
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- Authors
- Hsu, P.-H., Wei, K.-C., Huang, C.-Y., Wen, C.-J., Yen, T.-C., Liu, C.-L., Lin, Y.-T., Chen, J.-C., Shen, C.-R., & Liu, H.-L.
- Affiliations
- Chang Gung University (TW)
- Ming Chi University of Technology (TW)
- Corresponding author
- Shen, Chia-Rui
- Liu, Hao-Li
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-02-27
- Volume
- 8
- Issue
- 2
- Pages
- e57682
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3584045
- OpenAlex
- W1969401867
- Cited by
- 136
- References
- 57
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 9 · 2023: 4 · 2022: 12 · 2021: 20 · 2020: 12 · 2019: 12 · 2018: 12 · 2017: 3 · 2016: 9 · 2015: 14 · 2014: 13 · 2013: 2
- FWCI
- 6.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Science Council (100-2321-B-182-010)
- Chang Gung Medical Foundation
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- gene therapy, adeno-associated virus vectors, focused ultrasound, microbubbles, blood-brain barrier disruption, central nervous system disorders
- MeSH terms
- Dependovirus, Animals, Astrocytes, Blood-Brain Barrier, Brain, Contrast Media, Fluorescent Antibody Technique, Genetic Vectors, Magnetic Resonance Imaging, Male, Mice, Inbred ICR, Transduction, Genetic, Ultrasonics, Blotting, Western, Reproducibility of Results, Gene Transfer Techniques, Microbubbles, Green Fluorescent Proteins, Mice
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