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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AAV9 can cross the blood-brain barrier and transduce both neurons and astrocytes after intravenous administration.
“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]
AAV8 and AAV5 transduce a significantly greater area of the CNS in comparison with AAV2.
“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]
The Introduction (page unavailable) says AAV8 showed poor CNS penetration after vascular delivery, but it does not compare AAV8 with AAV2. Searches for AAV5, AAV2, and CNS transduction area found no passage comparing the three serotypes or reporting a significant difference. (LLM, conf=0.77)
Experimental — accuracy not yet measuredIn SMA murine models, systemically delivered self-complementary AAV9 crossed the blood brain barrier and achieved high levels of neuronal transduction.
“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]
The discovery of newer AAV capsids, such as AAV9, has permitted a much wider degree of gene transfer than multiple stereotaxic injections.
“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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Adeno-Associated Virus Serotype 9 Transduction in the Central Nervous System of Nonhuman Primates
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“Studies by us (Foust et al., 2009) and others (Duque et al.”
InfluentialSelf-citationIntravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice
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“An independent study similarly demonstrated the high potential of self-complementary AAV of serotype 9 (scAAV9) for neuronal transduction, albeit only in neonatal mice (9).”
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Adeno-Associated Virus-Based Gene Therapy for CNS Diseases
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Viral vectors for gene delivery to the central nervous system
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Intracellular transport of recombinant adeno-associated virus vectors
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“[143] AAV9 vectors are well tolerated IV viral vectors that can cross the endothelial cells of the BBB [144,145] via active-transport, while not compromising barrier integrity [146] and have promising results in clinical trials for their safety and their efficiency to transduce target cells, for example, in spinal mus…”
BackgroundReactive astrocytes and therapeutic potential in focal ischemic stroke
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Progress in gene therapy for neurological disorders
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“…et al, 2000; Cearley & Wolfe, 2006; de Backer et al, 2010; Markakis et al, 2010; Shen et al, 2013), and some of them (e.g., AAV9, AAVrh.8, and AAVrh.10) seem to be able to cross the mature BBB after systemic administration in adult animals (Foust et al, 2009; Dayton et al, 2012; Yang et al, 2014).”
BackgroundA single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse
Porensky, P. N., Mitrpant, C., McGovern, V. L., Bevan, A. K., Foust, K. D., Kaspar, B. K., Wilton, S. D., & Burghes, A. H. M. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr600 · Cited by 248 · see citing works
“FV injection on was performed as previously described (78).”
MethodSelf-citationErratum: Gene therapy for neurological disorders: progress and prospects
Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M., & Sah, D. W. Y. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.158 · Cited by 248 · see citing works
Emptying the stores: lysosomal diseases and therapeutic strategies
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“The discovery that AAV9 can be administered intravenously and it can correct the periphery and cross the blood-brain barrier raises the prospect of much less invasive gene therapy delivery in the future [89].”
BackgroundMECP2 disorders: from the clinic to mice and back
Lombardi, L. M., Baker, S. A., & Zoghbi, H. Y. (2015) · Journal of Clinical Investigation · doi:10.1172/jci78167 · Cited by 221 · see citing works
Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy
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“Asymmetrical distribution of AAV-neutralizing antibodies across the BBB .”
InfluentialEfficient prime editing in mouse brain, liver and heart with dual AAVs
Davis, J. R., Banskota, S., Levy, J. M., Newby, G. A., Wang, X., Anzalone, A. V., Nelson, A. T., Chen, P. J., Hennes, A. D., An, M., et al. (2023) · Nature Biotechnology · doi:10.1038/s41587-023-01758-z · Cited by 237 · see citing works
Structural insight into the unique properties of adeno-associated virus serotype 9
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Basic Biology of Adeno-Associated Virus (AAV) Vectors Used in Gene Therapy
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“Based on in vivo studies, vectors specific to retina (AAV2, AAV4 and AAV5) [64-68], brain (AAV2, AAV5, AAV8, AAV9 and AAVrh10) [69-78], cardiac tissue (AAV1, AAV2, AAV6, AAV8 and AAV9) [79-83], liver (AAV1, AAV2, AAV5, AAV6, AAV7, AAV8, AAV9 and AAV10) [49, 84-93] and lungs (AAV1, AAV2, AAV5 and AAV9) [86-89, 92-98] h…”
Engineering Liver-detargeted AAV9 Vectors for Cardiac and Musculoskeletal Gene Transfer
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Protective Functions of Reactive Astrocytes Following Central Nervous System Insult
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Garg†, S. K., Lioy, D. T., Cheval, H., McGann, J. C., Bissonnette, J. M., Murtha, M. J., Foust, K. D., Kaspar, B. K., Bird, A. P., & Mandel, G. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.1854-13.2013 · Cited by 220 · see citing works
“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 · see citing works
“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).”
A Historical Review of Brain Drug Delivery
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In vivo SELEX for Identification of Brain-penetrating Aptamers
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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 · see citing works
“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 207 · see citing works
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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…”
BackgroundFoust, 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 205 · see citing works
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 206 · see citing works
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“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 · see citing works
Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice
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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 · see citing works
“…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).”
BackgroundMolecular 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 · see citing works
The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice
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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 192 · see citing works
“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 · see citing works
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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 · see citing works
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 · see citing works
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 177 · see citing works
“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 177 · see citing works
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 · see citing works
Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 166 · see citing works
“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 · see citing works
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 169 · see citing works
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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 166 · see citing works
“Recombinant AAV1 vectors were produced by a standard triple-transfection calcium phosphate precipitation method using human embryonic kidney 293 cells (44, 45 ).”
MethodSelf-citationChaytow, H., Faller, K. M. E., Huang, Y.-T., & Gillingwater, T. H. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100346 · Cited by 171 · see citing works
“) 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 · see citing works
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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
- 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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