Exosome-associated AAV vector as a robust and convenient neuroscience tool
Open accessAbstract
Adeno-associated virus (AAV) vectors are showing promise in gene therapy trials and have proven to be extremely efficient biological tools in basic neuroscience research. One major limitation to their widespread use in the neuroscience laboratory is the cost, labor, skill and time-intense purification process of AAV. We have recently shown that AAV can associate with exosomes (exo-AAV) when the vector is isolated from conditioned media of producer cells, and the exo-AAV is more resistant to neutralizing anti-AAV antibodies compared with standard AAV. Here, we demonstrate that simple pelleting of exo-AAV from media via ultracentrifugation results in high-titer vector preparations capable of efficient transduction of central nervous system (CNS) cells after systemic injection in mice. We observed that exo-AAV is more efficient at gene delivery to the brain at low vector doses relative to conventional AAV, even when derived from a serotype that does not normally efficiently cross the blood-brain barrier. Similar cell types were transduced by exo-AAV and conventionally purified vector. Importantly, no cellular toxicity was noted in exo-AAV-transduced cells. We demonstrated the utility and robustness of exo-AAV-mediated gene delivery by detecting direct GFP fluorescence after systemic injection, allowing three-dimensional reconstruction of transduced Purkinje cells in the cerebellum using ex vivo serial two-photon tomography. The ease of isolation combined with the high efficiency of transgene expression in the CNS, may enable the widespread use of exo-AAV as a neuroscience research tool. Furthermore, the ability of exo-AAV to evade neutralizing antibodies while still transducing CNS after peripheral delivery is clinically relevant.
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Exosome-enveloped AAV8 or AAV9 have enhanced CNS transduction after intravenous injection.
“It is reported that exosome-enveloped AAV8 or AAV9 had enhanced CNS transduction after intravenous injection [146, 147].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [147]
Exosome-enveloped AAVs can transduce target cells in the presence of pre-existing immunity, induce tolerance, and confer altered tropism to AAV.
“In addition to chemically modified capsids, multiple studies showed exosome-enveloped AAVs can transduce the target cells in the presence of pre-existing immunity, induce tolerance, and confer altered tropism to AAV.”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [201]
Two other studies showed that exosome-encapsulated AAV8 and AAV9 had comparable or improved infectivity in addition to having 3 to 23-fold higher resistance to NAbs.
“Two other studies showed that exosome-encapsulated AAV8 and AAV9 had comparable or improved infectivity in addition to having 3 to 23-fold higher resistance to NAbs (143, 144).”
From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [143]
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- Authors
- Hudry, E., Martin, C., Gandhi, S., György, B., Scheffer, D. I., Mu, D., Merkel, S. F., Mingozzi, F., Fitzpatrick, Z., Dimant, H., Masek, M., Ragan, T., Tan, S., Brisson, A. R., Ramirez, S. H., Hyman, B. T., & Maguire, C. A.
- Affiliations
- Harvard University (US)
- Temple University (US)
- Genethon (France) (FR)
- TissueVision (United States) (US)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Maguire, C A
- ORCID
- Venue
- Gene Therapy
- Published
- 2016-02-02
- Volume
- 23
- Issue
- 4
- Pages
- 380-392
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC4824662
- OpenAlex
- W2292311115
- Cited by
- 146
- References
- 41
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 14 · 2023: 18 · 2022: 9 · 2021: 20 · 2020: 16 · 2019: 13 · 2018: 14 · 2017: 14 · 2016: 4
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-11-03)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- HAL (submittedVersion)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
- Funders
- National Institute on Aging (K99AG047336, R00AG047336, RF1AG047644)
- National Institute on Drug Abuse (P30DA013429)
- National Institute of Neurological Disorders and Stroke (R21NS081374, R01NS086570, NIH/NINDS R01 NS086570-01, P30NS045776, NIH/NINDS R21 NS081374-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- adeno-associated virus vectors, exosomes, AAV purification, neutralizing antibodies, blood-brain barrier, systemic injection, Purkinje cells, cerebellum, transduction efficiency
- MeSH terms
- Dependovirus, Animals, Blood-Brain Barrier, Brain, Cell Line, Genetic Vectors, Humans, Transduction, Genetic, Genetic Therapy, Gene Transfer Techniques, Transgenes, Mice, Exosomes, Antibodies, Neutralizing
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