Trafficking of adeno‐associated virus vectors across a model of the blood–brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells
Open accessAbstract
Developing therapies for central nervous system (CNS) diseases is exceedingly difficult because of the blood–brain barrier (BBB). Notably, emerging technologies may provide promising new options for the treatment of CNS disorders. Adeno‐associated virus serotype 9 (AAV 9) has been shown to transduce cells in the CNS following intravascular administration in rodents, cats, pigs, and non‐human primates. These results suggest that AAV 9 is capable of crossing the BBB. However, mechanisms that govern AAV 9 transendothelial trafficking at the BBB remain unknown. Furthermore, possibilities that AAV 9 may transduce brain endothelial cells or affect BBB integrity still require investigation. Using primary human brain microvascular endothelial cells as a model of the human BBB, we performed transduction and transendothelial trafficking assays comparing AAV 9 to AAV 2, a serotype that does not cross the BBB or transduce endothelial cells effectively in vivo. Results of our in vitro studies indicate that AAV 9 penetrates brain microvascular endothelial cells barriers more effectively than AAV 2, but has reduced transduction efficiency. In addition, our data suggest that (i) AAV 9 penetrates endothelial barriers through an active, cell‐mediated process, and (ii) AAV 9 fails to disrupt indicators of BBB integrity such as transendothelial electrical resistance, tight junction protein expression/localization, and inflammatory activation status. Overall, this report shows how human brain endothelial cells configured in BBB models can be utilized for evaluating transendothelial movement and transduction kinetics of various AAV capsids. Importantly, the use of a human in vitro BBB model can provide import insight into the possible effects that candidate AVV gene therapy vectors may have on the status of BBB integrity. image Read the Editorial Highlight for this article on page 192.
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Ramirez and colleagues demonstrated that AAV9 preferably crossed brain-endothelial barriers through an active, cell-mediated process, while little transduced endothelial cells.
“Ramirez and colleagues [115] demonstrated that AAV9 preferably crossed brain-endothelial barriers through an active, cell-mediated process, while little transduced endothelial cells.”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [115]
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- Authors
- Merkel, S. F., Andrews, A. M., Lutton, E. M., Mu, D., Hudry, E., Hyman, B. T., Maguire, C. A., & Ramirez, S. H.
- Affiliations
- Temple University (US)
- Massachusetts General Hospital (US)
- Department of Neurology The Massachusetts General Hospital Charlestown Massachusetts USA
- Harvard University (US)
- Corresponding author
- Maguire, Casey A.
- Ramirez, Servio H.
- ORCID
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2016-12-15
- Volume
- 140
- Issue
- 2
- Pages
- 216-230
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC5298820
- OpenAlex
- W2528854795
- Cited by
- 132
- References
- 8
- Citations by year
- 2026: 15 · 2025: 8 · 2024: 16 · 2023: 13 · 2022: 17 · 2021: 20 · 2020: 11 · 2019: 12 · 2018: 12 · 2017: 6 · 2016: 1
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Brain Tumor Association
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- AAV9, AAV2, blood-brain barrier, transcytosis, brain microvascular endothelial cells, transduction efficiency, blood-brain barrier integrity, tight junctions, transendothelial electrical resistance, gene therapy vectors, central nervous system gene therapy
- MeSH terms
- Dependovirus, Blood-Brain Barrier, Brain, Cell Movement, Cells, Cultured, Humans, Tight Junctions, Endothelial Cells, Transcytosis
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