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Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes
Open accessAbstract
Delivery of genes to the brain and spinal cord across the blood-brain barrier (BBB) has not yet been achieved. Here we show that adeno-associated virus (AAV) 9 injected intravenously bypasses the BBB and efficiently targets cells of the central nervous system (CNS). Injection of AAV9-GFP into neonatal mice through the facial vein results in extensive transduction of dorsal root ganglia and motor neurons throughout the spinal cord and widespread transduction of neurons throughout the brain, including the neocortex, hippocampus and cerebellum. In adult mice, tail vein injection of AAV9-GFP leads to robust transduction of astrocytes throughout the entire CNS, with limited neuronal transduction. This approach may enable the development of gene therapies for a range of neurodegenerative diseases, such as spinal muscular atrophy, through targeting of motor neurons, and amyotrophic lateral sclerosis, through targeting of astrocytes. It may also be useful for rapid postnatal genetic manipulations in basic neuroscience studies.
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“In addition, AAV9 vectors have the unique ability to cross the blood–brain-barrier and target the brain upon intravenous injection in adult mice and cats (Duque et al, 2009; Foust et al, 2009).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Foust et al, 2009
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Immunohistochemistry with anti-eGFP antibodies at 1 month PI, showed a viral transduction efficiency of 20–50% of eGFP-positive cells depending on the tissue (Supporting Information Fig S1E and F) (Foust et al, 2009; Inagaki et al, 2006; Zincarelli et al, 2008).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Foust et al, 2009
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“AAV9 can cross the blood–brain barrier and transduce both neurons and astrocytes after intravenous administration.7,10–11”
From Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism (2016) · cites this paper as [11]
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In the citing paper
“AAV8 and AAV5 transduce a significantly greater area of the CNS in comparison with AAV2”
From Characterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism (2016) · cites this paper as [11]
Experimental — accuracy not yet measuredIn the citing paper
“It was confirmed in SMA murine models that systemically delivered self-complementary AAV9 (scAAV9) crossed the blood brain barrier and achieved high levels of neuronal transduction.9,10”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [9]
In the citing paper
“The discovery of newer AAV capsids, such as AAV9, have permitted a much wider degree of gene transfer than multiple stereotaxic injections.9,10,67, 68, 69”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [9]
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Citations
Cites
Astrocyte-endothelial interactions at the blood-brain barrier
Abbott, N. J., Rönnbäck, L., & Hansson, E. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1824 · Cited by 5,595
Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis
Yamanaka, K., Chun, S. J., Boillee, S., Fujimori-Tonou, N., Yamashita, H., Gutmann, D. H., Takahashi, R., Misawa, H., & Cleveland, D. W. (2008) · Nature Neuroscience · doi:10.1038/nn2047 · Cited by 1,140 · cited 1×
“Our results also demonstrated efficient targeting of astrocytes in adult mice, and this finding may be relevant for treating ALS, where the non-cell autonomous nature of disease progression has recently been discovered, and astrocytes have been specifically linked to disease progressio”
ResultClades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues
Gao, G., Vandenberghe, L. H., Alvira, M. R., Lu, Y., Calcedo, R., Zhou, X., & Wilson, J. M. (2004) · Journal of Virology · doi:10.1128/jvi.78.12.6381-6388.2004 · Cited by 1,070 · cited 1×
“Neutralizing antibodies created against AAV serotypes 1–8 showed little to no cross-reactivity with AAV9, indicating that AAV9 is of a different AAV clad”
BackgroundKaplitt, M. G., Feigin, A., Tang, C., Fitzsimons, H. L., Mattis, P., Lawlor, P. A., Bland, R. J., Young, D., Strybing, K., Eidelberg, D., et al. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60982-9 · Cited by 1,067
Retrograde Viral Delivery of IGF-1 Prolongs Survival in a Mouse ALS Model
Kaspar, B. K., Lladó, J., Sherkat, N., Rothstein, J. D., & Gage, F. H. (2003) · Science · doi:10.1126/science.1086137 · Cited by 872 · cited 1×
“Gene therapy has been proposed as a means of crossing the BB”
BackgroundSelf-citationHarper, S. Q., Staber, P. D., He, X., Eliason, S. L., Martins, I. H., Mao, Q., Yang, L., Kotin, R. M., Paulson, H. L., & Davidson, B. L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501507102 · Cited by 682 · cited 1×
“It is noteworthy that AAV9 vascular delivery in the adult does not achieve widespread direct neuronal targeting, precluding the use of this approach for diseases such as Huntington's, in which multiple structures and brain regions are likely to require neuronal targeting to suppress mutant Huntingtin protei”
BackgroundGenetic influence on neurogenesis in the dentate gyrus of adult mice
Kempermann, G., Kuhn, H. G., & Gage, F. H. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.19.10409 · Cited by 638 · cited 1×
“Neuronal density and positive GFP density were calculated by multiplying the total volume to estimate the percent of neuronal transduction in each given area as previously describe”
MethodAdeno-associated virus serotype 8 efficiently delivers genes to muscle and heart
Wang, Z., Zhu, T., Qiao, C., Zhou, L., Wang, B., Zhang, J., Chen, C., Li, J., & Xiao, X. (2005) · Nature Biotechnology · doi:10.1038/nbt1073 · Cited by 622
Inagaki, K., Fuess, S., Storm, T. A., Gibson, G. A., Mctiernan, C. F., Kay, M. A., & Nakai, H. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.03.014 · Cited by 610
Marks, W. J., Ostrem, J. L., Verhagen, L., Starr, P. A., Larson, P. S., Bakay, R. A., Taylor, R., Cahn-Weiner, D. A., Stoessl, A. J., Olanow, C. W., et al. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70065-6 · Cited by 596
VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model
Azzouz, M., Ralph, G. S., Storkebaum, E., Walmsley, L. E., Mitrophanous, K. A., Kingsman, S. M., Carmeliet, P., & Mazarakis, N. D. (2004) · Nature · doi:10.1038/nature02544 · Cited by 588 · cited 1×
“Recent work in rodent models of SMA and ALS have demonstrated the potential of gene delivery using viruses that undergo retrograde transport after intramuscular injection, and this approach is currently being explored for clinical trial”
BackgroundMcCarty, D. M., Fu, H., Monahan, P. E., Toulson, C. E., Naik, P., & Samulski, R. J. (2003) · Gene Therapy · doi:10.1038/sj.gt.3302134 · Cited by 547
Directed evolution of adeno-associated virus yields enhanced gene delivery vectors
Maheshri, N., Koerber, J. T., Kaspar, B. K., & Schaffer, D. V. (2006) · Nature Biotechnology · doi:10.1038/nbt1182 · Cited by 538 · cited 1×
“However, viral evolution techniques may enable the generation of AAV9 variants that target adult neurons by vascular deliver”
BackgroundSelf-citationRalph, G. S., Radcliffe, P. A., Day, D. M., Carthy, J. M., Leroux, M. A., Lee, D. C. P., Wong, L., Bilsland, L. G., Greensmith, L., Kingsman, S. M., et al. (2005) · Nature Medicine · doi:10.1038/nm1205 · Cited by 507 · cited 1×
“Recent work in rodent models of SMA and ALS have demonstrated the potential of gene delivery using viruses that undergo retrograde transport after intramuscular injection, and this approach is currently being explored for clinical trial”
BackgroundDynamics of CNS Barriers: Evolution, Differentiation, and Modulation
Abbott, N. J. (2005) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-004-1374-y · Cited by 471 · cited 1×
“Given that astrocytes retain some features of apical-basal polarity from development, certain receptors or channels may be accessible by this vascular entry route but not by direct intraparenchymal injection”
BackgroundAkache, B., Grimm, D., Pandey, K., Yant, S. R., Xu, H., & Kay, M. A. (2006) · Journal of Virology · doi:10.1128/jvi.00878-06 · Cited by 448
Drug and gene targeting to the brain with molecular trojan horses
Pardridge, W. M. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd725 · Cited by 439 · cited 1×
“1515" language="eng" relation="no"> Nearly all large-molecule drugs and ∼98% of small-molecule drugs do not cross the BBB, limiting the development of drugs for many disorders of the CN”
BackgroundCearley, C. N., & Wolfe, J. H. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2005.11.015 · Cited by 409
Recombinant Adeno-Associated Virus Serotype 9 Leads to Preferential Cardiac Transduction In Vivo
Pacak, C. A., Mah, C. S., Thattaliyath, B. D., Conlon, T. J., Lewis, M. A., Cloutier, D. E., Zolotukhin, I., Tarantal, A. F., & Byrne, B. J. (2006) · Circulation Research · doi:10.1161/01.res.0000237661.18885.f6 · Cited by 406
Worgall, S., Sondhi, D., Hackett, N. R., Kosofsky, B., Kekatpure, M. V., Neyzi, N., Dyke, J. P., Ballon, D., Heier, L., Greenwald, B. M., et al. (2008) · Human Gene Therapy · doi:10.1089/hum.2008.022 · Cited by 402 · cited 1×
“AAV vectors such as AAV2 have shown promise in several recent clinical trials for neurological disorders, demonstrating sustained transgene expression, a relatively safe profile and promising functional responses, yet have required surgical intraparenchymal injection”
BackgroundUnrestricted Hepatocyte Transduction with Adeno-Associated Virus Serotype 8 Vectors in Mice
Nakai, H., Fuess, S., Storm, T. A., Muramatsu, S., Nara, Y., & Kay, M. A. (2004) · Journal of Virology · doi:10.1128/jvi.79.1.214-224.2005 · Cited by 335
Rodríguez-Lebrón, E., Denovan‐Wright, E. M., Nash, K. R., Lewin, A. S., & Mandel, R. J. (2005) · Molecular Therapy · doi:10.1016/j.ymthe.2005.05.006 · Cited by 279
Haidet, A. M., Rizo, L., Handy, C. R., Umapathi, P., Eagle, A., Shilling, C., Boué, D. R., Martin, P. T., Sahenk, Z., Mendell, J. R., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709144105 · Cited by 274
Self-citationLi, W., Asokan, A., Wu, Z., Van Dyke, T., DiPrimio, N., Johnson, J. S., Govindaswamy, L., Agbandje-McKenna, M., Leichtle, S., Eugene Redmond Jr, D., et al. (2008) · Molecular Therapy · doi:10.1038/mt.2008.100 · Cited by 261
Efficient transduction of skeletal muscle using vectors based on adeno-associated virus serotype 6
Blankinship, M. J., Gregorevic, P., Allen, J. M., Harper, S. Q., Harper, H. A., Halbert, C. L., Miller, A. D., & Chamberlain, J. S. (2004) · Molecular Therapy · doi:10.1016/j.ymthe.2004.07.016 · Cited by 259
Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy
Azzouz, M., Le, T. T., Ralph, G. S., Walmsley, L. E., Monani, U. R., Lee, D. C. P., Wilkes, F. J., Mitrophanous, K. A., Kingsman, S. M., Burghes, A. H. M., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22922 · Cited by 209 · cited 1×
“Recent work in rodent models of SMA and ALS have demonstrated the potential of gene delivery using viruses that undergo retrograde transport after intramuscular injection, and this approach is currently being explored for clinical trial”
BackgroundKlein, R. L., Dayton, R. D., Tatom, J. B., Henderson, K. M., & Henning, P. P. (2008) · Molecular Therapy · doi:10.1038/sj.mt.6300331 · Cited by 196
Expanded Repertoire of AAV Vector Serotypes Mediate Unique Patterns of Transduction in Mouse Brain
Cearley, C. N., Vandenberghe, L. H., Parente, M. K., Carnish, E. R., Wilson, J. M., & Wolfe, J. H. (2008) · Molecular Therapy · doi:10.1038/mt.2008.166 · Cited by 182
DNA Shuffling of Adeno-associated Virus Yields Functionally Diverse Viral Progeny
Koerber, J. T., Jang, J.-H., & Schaffer, D. V. (2008) · Molecular Therapy · doi:10.1038/mt.2008.167 · Cited by 181
Miller, T. M., Kim, S. H., Yamanaka, K., Hester, M. E., Umapathi, P., Arnson, H. A., Rizo, L., Mendell, J. R., Gage, F. H., Cleveland, D. W., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609411103 · Cited by 172
Self-citationDodge, J. C., Haidet, A. M., Yang, W., Passini, M. A., Hester, M. E., Clarke, J., Roskelley, E. M., Treleaven, C. M., Rizo, L., Martin, H. L., et al. (2008) · Molecular Therapy · doi:10.1038/mt.2008.60 · Cited by 160
Self-citationTargeted Retrograde Gene Delivery for Neuronal Protection
Kaspar, B. K., Erickson, D. A., Schaffer, D. V., Hinh, L., Gage, F. H., & Peterson, D. A. (2002) · Molecular Therapy · doi:10.1006/mthe.2001.0520 · Cited by 147
Self-citationTowne, C. L., Raoul, C., Schneider, B. L., & Aebischer, P. (2008) · Molecular Therapy · doi:10.1038/mt.2008.73 · Cited by 137
Efficient Retrograde Neuronal Transduction Utilizing Self-complementary AAV1
Hollis, E. R., II, Kadoya, K., Hirsch, M. L., Samulski, R. J., & Tuszynski, M. H. (2008) · Molecular Therapy · doi:10.1038/sj.mt.6300367 · Cited by 126
Foust, K. D., Poirier, A. E., Pacak, C. A., Mandel, R. J., & Flotte, T. R. (2007) · Human Gene Therapy · doi:10.1089/hum.2007.093 · Cited by 79
Self-citationStimulating Full-Length SMN2 Expression by Delivering Bifunctional RNAs via a Viral Vector
Baughan, T. D., Shababi, M., Coady, T. H., Dickson, A., Tullis, G. E., & Lorson, C. L. (2006) · Molecular Therapy · doi:10.1016/j.ymthe.2006.01.012 · Cited by 73
Francis Crick's Legacy for Neuroscience: Between the α and the Ω
Siegel, R. M., & Callaway, E. M. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020419 · Cited by 9
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Metadata
- Authors
- Foust, K. D., Nurre, E., Montgomery, C. L., Hernandez, A., Chan, C. M., & Kaspar, B. K.
- Affiliations
- Nationwide Children's Hospital (US)
- Corresponding author
- Kaspar, Brian K
- Venue
- Nature Biotechnology
- Published
- 2008-12-21
- Volume
- 27
- Issue
- 1
- Pages
- 59-65
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC2895694
- OpenAlex
- W2166739815
- Cited by
- 1,456
- References
- 38
- Citations by year
- 2026: 75 · 2025: 91 · 2024: 107 · 2023: 94 · 2022: 87 · 2021: 101 · 2020: 105 · 2019: 90 · 2018: 100 · 2017: 81 · 2016: 79 · 2015: 78 · 2014: 74 · 2013: 88 · 2012: 54
- FWCI
- 28.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (R21EY018491)
- National Institute of Neurological Disorders and Stroke (R21NS064328, R01NS064492)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- AAV9, adeno-associated virus, blood-brain barrier, astrocytes, motor neurons, neonatal neurons, spinal cord, dorsal root ganglia, gene therapy, spinal muscular atrophy, amyotrophic lateral sclerosis
- MeSH terms
- Dependovirus, Animals, Astrocytes, Ganglia, Spinal, Genetic Vectors, Hippocampus, Mice, Inbred C57BL, Muscular Atrophy, Spinal, Neurons, In Situ Hybridization, Gene Transfer Techniques, Transgenes, Neocortex, Green Fluorescent Proteins, Mice
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