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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.
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“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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“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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Protective Functions of Reactive Astrocytes Following Central Nervous System Insult
Linnerbauer, M., & Rothhammer, V. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.573256 · Cited by 235
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“Two strong advantages are that it crosses the blood– brain barrier and infects both neuronal and non-neuronal cells in the brain (Foust et al., 2009; Gray et al., 2011).”
BackgroundInfluentialSelf-citationSpinal muscular atrophy: mechanisms and therapeutic strategies
Lorson, C. L., Rindt, H., & Shababi, M. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq147 · Cited by 209
“Blood–brain barrier penetration is an impediment for all CNS disorders, especially for vectorbased technology; however, with the analysis of new serotypes, exciting CNS penetration from an IV injection has been accomplished using AAV-9 (84,85).”
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“Asymmetrical distribution of AAV-neutralizing antibodies across the BBB .”
InfluentialIn vivo SELEX for Identification of Brain-penetrating Aptamers
Cheng, C., Chen, Y. H., Lennox, K. A., Behlke, M. A., & Davidson, B. L. (2013) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2012.59 · Cited by 215
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“Studies in adult animals, however, demonstrated significantly restricted entry of viral particles into the CNS and declined transduction efficiency due to the advanced BBB development [15, 23].”
BackgroundInfluentialBevan, A. K., Hutchinson, K. R., Foust, K. D., Braun, L., McGovern, V. L., Schmelzer, L., Ward, J. G., Petruska, J. C., Lucchesi, P. A., Burghes, A. H. M., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq300 · Cited by 211
“To do this, we injected neonatal WT animals with scAAV9 carrying a GFP transgene to visualize which tissues were transduced (33).”
MethodSelf-citationAdeno-Associated Virus Technologies and Methods for Targeted Neuronal Manipulation
Haery, L., Deverman, B. E., Matho, K. S., Cetin, A. H., Woodard, K., Cepko, C. L., Guerin, K. I., Rego, M. A., Ersing, I., Bächle, S. M., et al. (2019) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2019.00093 · Cited by 220
Influence of Pre-existing Anti-capsid Neutralizing and Binding Antibodies on AAV Vector Transduction
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“INTRODUCTION Systemic administration of adeno-associated virus (AAV) vectors has been utilized in preclinical studies to transduce a number of tissues, including liver parenchyma, skeletal muscle,(4,5) and CNS.(6) Recent promising data from hemophilia clinical trials have confirmed that peripheral administration of AA…”
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Foust, K. D., Salazar, D. L., Likhite, S. B., Ferraiuolo, L., Ditsworth, D., Ilieva, H. S., Meyer, K., Schmelzer, L., Braun, L., Cleveland, D. W., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.211 · Cited by 211
Self-citationAAV-based in vivo gene therapy for neurological disorders
Ling, Q., Herstine, J. A., Bradbury, A. M., & Gray, S. J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00766-7 · Cited by 223
Thévenot, E., Jordão, J. F., O’Reilly, M. A., Markham, K. A., Weng, Y., Foust, K. D., Kaspar, B. K., Hynynen, K., & Aubert, I. (2012) · Human Gene Therapy · doi:10.1089/hum.2012.013 · Cited by 202
“In the striatum, our data indicate a preferential expression of the GFP transgene in astrocytes, as previously reported (Foust et al., 2009).”
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Gene therapy for the CNS using AAVs: The impact of systemic delivery by AAV9
Saraiva, J., Nobre, R. J., & Pereira de Almeida, L. (2016) · Journal of Controlled Release · doi:10.1016/j.jconrel.2016.09.011 · Cited by 201
Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice
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Molecular evolution of adeno-associated virus for enhanced glial gene delivery
Koerber, J. T., Klimczak, R., Jang, J.-H., Dalkara, D., Flannery, J. G., & Schaffer, D. V. (2009) · Molecular Therapy · doi:10.1038/mt.2009.184 · Cited by 181
Viral vectors for therapy of neurologic diseases
Choudhury, S. R., Hudry, E., Maguire, C. A., Sena-Esteves, M., Breakefield, X. O., & Grandi, P. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.02.013 · Cited by 190
“…that injection of AAV9 at P0 (post-natal day 0) in mice results in widespread neuronal transduction, while administration at older ages results primarily in glial and endothelial cell transduction (IV: Foust et al., 2009; Bevan et al., 2011; Samaranch et al., 2012; ICV: Chakrabarty et al., 2013).”
BackgroundThe AAV9 receptor and its modification to improve in vivo lung gene transfer in mice
Bell, C. L., Vandenberghe, L. H., Bell, P., Limberis, M. P., Gao, G.-P., Van Vliet, K., Agbandje-McKenna, M., & Wilson, J. M. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57367 · Cited by 190
Gene therapy for ALS: A review
Amado, D. A., & Davidson, B. L. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2021.04.008 · Cited by 203
“administration in SOD1 mice at differing ages and found a 39% increase in survival after P1-injection that decreased substantially with age and disease progression;(116) they noted increasingly preferential glial targeting over neurons with later injections.(116,117) They also found markedly increased survival in the…”
BackgroundViral Strategies for Targeting the Central and Peripheral Nervous Systems
Bedbrook, C. N., Deverman, B. E., & Gradinaru, V. (2018) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-080317-062048 · Cited by 168
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Al-Zaidy, S. A., & Mendell, J. R. (2019) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2019.06.007 · Cited by 189
In vivo genome editing improves motor function and extends survival in a mouse model of ALS
Gaj, T., Ojala, D. S., Ekman, F. K., Byrne, L. C., Limsirichai, P., & Schaffer, D. V. (2017) · Science Advances · doi:10.1126/sciadv.aar3952 · Cited by 185
Development of Novel Therapeutics Targeting the Blood–Brain Barrier: From Barrier to Carrier
Li, J., Zheng, M., Shimoni, O., Banks, W. A., Bush, A. I., Gamble, J. R., & Shi, B. (2021) · Advanced Science · doi:10.1002/advs.202101090 · Cited by 202
Schuster, D. J., Dykstra, J. A., Riedl, M. S., Kitto, K. F., Belur, L. R., McIvor, R. S., Elde, R. P., Fairbanks, C. A., & Vulchanova, L. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00042 · Cited by 161
“Whereas the intravenous route of delivery of AAV9 has been examined extensively and successfully utilized in models of neurological disorders (Foust et al., 2009; Fu et al., 2011; Ruzo et al., 2012; Garg et al., 2013; Shen et al., 2013; Yamashita et al., 2013; Elmallah et al., 2014), AAV9…”
BackgroundMethodInfluentialDirect Neuronal Reprogramming: Achievements, Hurdles, and New Roads to Success
Gascón, S., Masserdotti, G., Russo, G. L., & Götz, M. (2017) · Cell stem cell · doi:10.1016/j.stem.2017.06.011 · Cited by 183
Matsuzaki, Y., Konno, A., Mochizuki, R., Shinohara, Y., Nitta, K., Okada, Y., & Hirai, H. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2017.11.049 · Cited by 173
Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
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“Perhaps another alternative would be to use gene therapy vectors to deliver a beneficial (E2) or even the neutral form (E3) of APOE, using specific AAV capsid serotypes that are preferentially neurotropic even when administered in the periphery [220, 221].”
BackgroundRobust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs
Federici, T., Taub, J. S., Baum, G. R., Gray, S. J., Grieger, J. C., Matthews, K. A., Handy, C. R., Passini, M. A., Samulski, R. J., & Boulis, N. M. (2011) · Gene Therapy · doi:10.1038/gt.2011.130 · Cited by 169
Lafora disease — from pathogenesis to treatment strategies
Nitschké, F., Ahonen, S., Nitschke, S., Mitra, S., & Minassian, B. A. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0057-0 · Cited by 174
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Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates
Kota, J., Handy, C. R., Haidet, A. M., Montgomery, C. L., Eagle, A., Rodino‐Klapac, L. R., Tucker, D., Shilling, C. J., Therlfall, W. R., Walker, C. M., et al. (2009) · Science Translational Medicine · doi:10.1126/scitranslmed.3000112 · Cited by 174
“Recombinant AAV1 vectors were produced by a standard triple-transfection calcium phosphate precipitation method using human embryonic kidney 293 cells (44, 45 ).”
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“) injection of adeno-associated viral vector serotype 9 (AAV9)-based gene transfer can cross the blood-brain barrier (BBB)(31) and efficiently transduce target cells in the CNS, including motor neurons in the spinal cord in mice and non-human primates.(31,32) Development of the self-complementary AAV9 (scAAV9) vector…”
BackgroundFetal gene therapy for neurodegenerative disease of infants
Massaro, G., Mattar, C. N. Z., Wong, A. M. S., Sirka, E., Buckley, S. M. K., Herbert, B. R., Karlsson, S., Perocheau, D. P. B., Burke, D. G., Heales, S., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0106-7 · Cited by 160
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“However, it was also reported that AAV9 crosses the blood brain barrier when delivered intravascularly and targets neurons in neonatal mice but then expresses in astrocytes in adult mice [32].”
Background
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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