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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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“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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Cites
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“Gene therapy has been proposed as a means of crossing the BB”
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“That changed when Foust et al. (2009) demonstrated green fluorescent protein expression throughout the mouse CNS with intravenous AAV9 vector administration.”
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Bemelmans, A., Duqué, S. I., Rivière, C., Astord, S., Desrosiers, M., Marais, T., Sahel, J., Voït, T., & Barkats, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061618 · Cited by 18
“The demonstration of broad gene delivery to neurons after systemic scAAV9 injection [24,25] and the therapeutic proof-of-principle of this method in a mouse model of SMA [27–29] have paved the way for the clinical development of intravenous scAAV9 gene therapy for”
MethodSorrentino, N. C., Maffia, V., Strollo, S., Cacace, V., Romagnoli, N., Manfredi, A., Ventrella, D., Dondi, F., Barone, F., Giunti, M., et al. (2015) · Molecular Therapy · doi:10.1038/mt.2015.212 · Cited by 18
Targeting delivery in Parkinson's disease
Newland, B., Dunnett, S. B., & Dowd, E. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.06.003 · Cited by 17
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Genetic therapies for neurological disorders
FitzPatrick, L., & Bird, A. P. (2021) · Human Genetics · doi:10.1007/s00439-021-02399-5 · Cited by 19
Imaging Net Retrograde Axonal Transport In Vivo: A Physiological Biomarker
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“latter findings are consistent with earlier evidence that AAV9 vectors preferentially transfect motor neurons.(38) At day 85, net retrograde axonal transport was fully preserved in the CRISPR-treated SOD1 mice and distinctly better than in untreated mice (Fig 4, Video VIDEO S2, Table S1).”
ResultWu, J., & Heger, C. (2022) · Green Analytical Chemistry · doi:10.1016/j.greeac.2022.100027 · Cited by 16
Han, J., Zhu, L., Zhang, J., Guo, L., Sun, X., Huang, C., Xu, K., Zhang, Y., Li, W., & Zhou, Q. (2022) · Cell Proliferation · doi:10.1111/cpr.13339 · Cited by 17
Adeno-associated virus vector-based gene therapies for pediatric diseases
Muramatsu, K., & Muramatsu, S. (2022) · Pediatrics & Neonatology · doi:10.1016/j.pedneo.2022.09.004 · Cited by 16
“2 newborn mice resulted in highly efficient gene transfer to neurons in the spinal cord, and AAV9 became a target of interest as a gene transfer vector that can penetrate the bloodebrain barrier.(8) Then after, it was shown that intravenous administration of the AAV9 vector can transduce neurons in a wide range of reg…”
BackgroundAdvancements in Viral Gene Therapy for Gaucher Disease
Kulkarni, A., Chen, T., Sidransky, E., & Han, T. (2024) · Genes · doi:10.3390/genes15030364 · Cited by 16
“To measure the effectiveness of gene therapy for nGD, Massaro et al. developed an AAV9 vector with a human β -glucuronidase (GUSB) promoter [47].”
BackgroundMethodGene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.
Metovic, J., Li, Y., Gong, Y., & Eichler, F. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00443 · Cited by 16
“Other important CNS-speci fi c AAV capsid features include: 1) BBB penetrance, which allows less invasive IV delivery of CNS-targeted gene therapies [39,40]; 2) retrograde and anterograde axonal transport [41,42], which increases CNS transduction and targets leuko-axonopathies; and 3) non-human…”
BackgroundGene Therapy: The View from NCATS
Brooks, P. J., Yang, N. N., & Austin, C. P. (2016) · Human Gene Therapy · doi:10.1089/hum.2016.29018.pjb · Cited by 16
Sun, J., Hua, B., Chen, X., Samulski, R. J., & Li, C. (2017) · Human Gene Therapy · doi:10.1089/hum.2017.016 · Cited by 16
“As inhibitory antibodies would essentially reverse the therapeutic effects of transgenic FVIII, the potential benefits of delivering FVIIa using an alternative AAV serotype-AAV9, a serotype that evades neutralizing antibodies to AAV8, was investigated.(37) Although neutralizing antibodies to AAV8 showed low cross-reac…”
BackgroundNiemir, N., Rouvière, L., Besse, A., Vanier, M. T., Dmytrus, J., Marais, T., Astord, S., Puech, J.-P., Panasyuk, G., Cooper, J. D., et al. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy012 · Cited by 16
“Recombinant AAV9 vectors are promising tools due to their capacity to deliver a transgene to brain after neonatal intravenous administration (14, 15).”
BackgroundRNP Assembly Defects in Spinal Muscular Atrophy
Price, P. L., Morderer, D., & Rossoll, W. (2018) · Advances in neurobiology · doi:10.1007/978-3-319-89689-2_6 · Cited by 15
Enhancing the Therapeutic Potential of Sulfamidase for the Treatment of Mucopolysaccharidosis IIIA
Sorrentino, N. C., Cacace, V., Risi, M. D., Maffia, V., Strollo, S., Tedesco, N., Nusco, E., Romagnoli, N., Ventrella, D., Huang, Y., et al. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.10.009 · Cited by 16
“Among different AAV serotypes, serotype 9 has been shown to have a broad tropism, including neurons and astrocytes, when delivered either via CSF or through intravenous injection due to its capability to cross the blood-brain barrier (BBB).(18,19) We recently demonstrated that AAV9 outperforms all other AAV serotypes…”
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Tyrosine Mutation in AAV9 Capsid Improves Gene Transfer to the Mouse Lung
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Kagiava, A., Karaiskos, C., Lapathitis, G., Heslegrave, A., Sargiannidou, I., Zetterberg, H., Bosch, A., & Kleopa, K. A. (2023) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2023.07.011 · Cited by 15
Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease
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“Conse - quently, the AAV9 is of particular interest as it has been shown to pass the blood brain barrier in mice, leading to widespread transduction of the CNS, while simultaneously being less invasive than intracranial delivery [211, 271].”
BackgroundMassively parallel in vivo Perturb-seq screening
Zheng, X., Thompson, P. C., White, C., & Jin, X. (2025) · Nature Protocols · doi:10.1038/s41596-024-01119-3 · Cited by 17
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“More importantly, some natural AAVs, such as AAV9 and AAV-rh10, are able to cross the BBB and target the CNS via peripheral administration [7,9].”
Convection-Enhanced Delivery of AAV2-PrPshRNA in Prion-Infected Mice
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“In addition, AAV9 is capable to bypass the brain blood barrier (Foust et al. 2009), an important feature that may be utilized to treat a wide range of neural degenerations in the central never system.”
BackgroundAdvanced Fluorescence Protein-Based Synapse-Detectors
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BackgroundInfluentialSiu, J. J., Queen, N. J., Huang, W., Yin, F., Liu, X., Wang, C., McTigue, D. M., & Cao, L. (2017) · Gene Therapy · doi:10.1038/gt.2017.27 · Cited by 17
“Up to date AAV9 has become the most preferable serotype for spinal cord gene transfer (9-14).”
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“AAV9 has the ability to cross the BBB and the blood-spinal cord barrier following intravenous injection, leading to transgene expression primarily in astrocytes.(31) We found that AAV2-HBKO (1.”
BackgroundGhadge, G. D., Pavlovic, J. D., Koduvayur, S. P., Kay, B. K., & Roos, R. P. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.04.007 · Cited by 15
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“59,62,70,73,80,81 When delivered intravenously, AAV9 can traverse the BBB to target new-born neurons and adult glial cells, 29 and drive axonal transport.”
BackgroundAdvances and Challenges in the Development of Gene Therapy Medicinal Products for Rare Diseases
Bueren, J. A., & Auricchio, A. (2023) · Human Gene Therapy · doi:10.1089/hum.2023.152 · Cited by 17
“84 This unique ability has been instrumental to generate effective therapies for untreatable deadly diseases, such as spinal muscular atrophy or Duchenne muscular dystrophy (DMD) where affected tissues are hard to transduce due to the presence of physical barriers and/or require body-wide targeting…”
McDowall, S., Bagda, V., Hodgetts, S. I., Mastaglia, F. L., & Li, D. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00450-9 · Cited by 15
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“One type, AAV9 had been shown to effectively cross the BBB and preferentially infect astrocytes in adult mice and primates [177, 178], and designed promoters such as GFaABC1D which are only 681 bp, can be utilized to infect the same cells as GFAP and save space if the gene construct is large [179].”
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López‐Cortés, A., Echeverría‐Garcés, G., & Ramos-Medina, M. J. (2022) · Biology · doi:10.3390/biology11060894 · Cited by 16
“These features allow an efficient transduction of 60% of the motor neurons [90], without integrating into the host genome, and a fast and continued expression of SMN [91,92].”
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“The lower response noted with age was attributed possibly to the preferential astrocytic transfection reported following intravascular GTT delivery in animals as they mature [79].”
BackgroundProgress in gene and cell therapies for the neuronal ceroid lipofuscinoses
Donsante, A., & Boulis, N. M. (2018) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2018.1492544 · Cited by 14
“Given AAV9’s ability to cross the blood–brain barrier [39] and the initial success in the clinic of gene therapy for spinal muscular atrophy (SMA) [40], it would be interesting to see if a more complete protection could be achieved by intravenous delivery of this vector.”
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“, 2009) and better bypass the BBB when administered systemically (Foust et al., 2009).”
BackgroundEstablishment of a Pilot Newborn Screening Program for Spinal Muscular Atrophy in Saint Petersburg
Kiselev, A., Maretina, M. A., Shtykalova, S., Al-Hilal, H., Maslyanyuk, N. A., Plokhih, M., Serebryakova, E. A., Frolova, M., Shved, N. Y., Krylova, N., et al. (2024) · International Journal of Neonatal Screening · doi:10.3390/ijns10010009 · Cited by 13
“CB.SMN vector, which Foust et al. found crosses the blood-brain barrier [23].”
BackgroundOwusu-Yaw, B. S., Zhang, Y., Garrett, L., Yao, A., Shing, K., Batista, A. R., Sena‐Esteves, M., Upadhyay, J., Kegel-Gleason, K. B., & Todd, N. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16060710 · Cited by 17
“FUS-mediated delivery of AAV9-U6-miR10150 resulted in 0.2–13% of neurons and 0.04–4% of astrocytes being transduced.”
BackgroundMethodInfluentialRoberts, W. S., Price, S., Wu, M., & Parmar, M. S. (2024) · Cureus · doi:10.7759/cureus.67037 · Cited by 17
“To achieve this, ongoing research is focused on developing BBB-penetrating AAV capsids, exploring alternative delivery methods like nonviral vectors and focused ultrasound, and investigating strategies to open the BBB transiently [72,73].”
BackgroundLuo, N., Lin, K., Cai, Y., Zhang, Z., Sui, X., Han, Z., Yuan, W., Xing, J., Gui, Z., Liu, G., et al. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.01.021 · Cited by 14
Integrative approaches to enhance adeno-associated viral gene delivery
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“…system cells (i.e. beyond the blood–brain barrier) in animal models, when administered at a high dose (Bevan et al., 2011; Dayton, Wang, & Klein, 2012; Dominguez et al., 2011; Duque et al., 2009; Foust et al., 2009, 2010; Fu, Dirosario, Killedar, Zaraspe, & McCarty, 2011; Gray et al., 2011).”
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Motor Neuron Biology and Disease: A Current Perspective on Infantile-Onset Spinal Muscular Atrophy
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AAV Gene Transfer to the Heart
Wang, S., Guo, Y., & Pu, W. T. (2020) · Methods in molecular biology · doi:10.1007/978-1-0716-0668-1_20 · Cited by 12
Gene Therapy in Skeletal Muscle Mediated by Adeno-Associated Virus Vectors
Qiao, C., Koo, T., Li, J., Xiao, X., & Dickson, J. G. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-370-7_5 · Cited by 13
Innovating spinal muscular atrophy models in the therapeutic era
Signoria, I., van der Pol, W. L., & Groen, E. J. N. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.050352 · Cited by 14
“Preclinical studies performed in these models generated invaluable data on the efficacy, distribution and other key requirements of gene-targeting therapies (Foust et al., 2009; Hua et al., 2011; Zhao et al., 2021).”
Gene and Cellular Therapies for Leukodystrophies
Aerts‐Kaya, F., & van Til, N. P. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15112522 · Cited by 14
“Some AAV capsids, such as AAV9 and AAV.rh10, which have a predominant tropism for neurons but can also transduce astrocytes or oligodendrocytes, can be directly injected into the circulation and have the ability to cross the BBB [100,101].”
BackgroundLee, J., Chung, W. K., Pisapia, D. J., & Henderson, C. E. (2024) · Human Molecular Genetics · doi:10.1093/hmg/ddae190 · Cited by 12
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In vivo delivery systems for CRISPR genome editing: Viral and non-viral carriers
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Adeno-Associated Virus-Mediated Gene Therapy
Zaman, H., Khan, A. U., Khan, K., Toheed, S., Abdullah, M., Zeeshan, H. M., Hameed, A., Umar, M., Shahid, M., Malik, K. A., et al. (2023) · Critical Reviews in Eukaryotic Gene Expression · doi:10.1615/critreveukaryotgeneexpr.2023048135 · Cited by 12
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Gilkes, J. A., Bloom, M. D., & Heldermon, C. D. (2015) · Gene Therapy · doi:10.1038/gt.2015.111 · Cited by 11
“14 ,18 Several studies suggest an age dependent phenomenon for transduction patterns, 16,17,19,24 with rapid brain development possibly facilitating vector biodistribution.”
Epigenome Editing in the Brain
Bashtrykov, P., & Jeltsch, A. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-53889-1_21 · Cited by 12
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“Given the differences in transient hypothermia outcomes based on the route of administration and since previous studies have reported differences in the observed transduction efficiency of brain cells with the rAAV9 vector, possibly due to alternative intravenous routes of delivery [21,22], we decided to explore the p…”
BackgroundGene therapy for leukodystrophy: progress, challenges and opportunities
Aubourg, P. R. (2016) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2016.1151352 · Cited by 11
“cytes or neurons of brain and spinal cord.[54,55] Most of these results have however been obtained in mice and must be re-”
BackgroundCurrent trends in gene therapy to treat inherited disorders of the brain
Matuszek, Ż., Brown, B. L., Yrigollen, C. M., Keiser, M. S., & Davidson, B. L. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.03.057 · Cited by 13
“10,11 However, the majority of the transduced cells in the CNS were endothelial cells or astrocytes, and high levels of expression were seen in peripheral tissues including the liver, kidneys, and heart.”
Targeting the Root Cause of Mucopolysaccharidosis IIIA with a New scAAV9 Gene Replacement Vector
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“Adeno-associated virus serotype 9 (AAV9) has been applied to re-introduce wild-type (WT) MECP2 by intravenous injection in vivo, to extend the lifespan of Mecp2-/y mice [7].”
Cabrera, G. T., Meijboom, K. E., Abdallah, A., Tran, H., Foster, Z. W., Weiss, A., Wightman, N., Stock, R. E., Gendron, T. F., Gruntman, A. M., et al. (2023) · Gene Therapy · doi:10.1038/s41434-023-00418-w · Cited by 11
“We scored for total exon targets, cytoplasmic intron targets, and colocalized targets (Fig.”
Lang, Y., Wang, Q., Sheng, Q., Lu, S., Yang, M., Kong, Z., Gao, Y., Fan, X., Shen, N., Wang, R., et al. (2024) · The FASEB Journal · doi:10.1096/fj.202301419rr · Cited by 11
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Developing AAV-delivered nonsense suppressor tRNAs for neurological disorders
Wang, J., Gao, G., & Wang, D. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00391 · Cited by 10
“In this regard, AAV9 is arguably the most ef fi cient naturally occurring serotype [129 – 131], and generally considered as the benchmark when characterizing novel capsids.”
BackgroundA brief guide for gene delivery to the brain using adeno-associated viral vectors
Han, S., Yang, E. M., & Hur, E. (2025) · Molecules and Cells · doi:10.1016/j.mocell.2025.100189 · Cited by 13
Optimized AAV capsids for basal ganglia diseases show robust potency and distribution
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Transduction of Salivary Gland Acinar Cells with a Novel AAV Vector 44.9
Pasquale, G. D., Riveros, P. P., Tora, M. S., Sheikh, T., Son, A., Teos, L. Y., Grewe, B., Swaim, W. D., Afione, S. A., Zheng, C., et al. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.10.006 · Cited by 12
Lopes, M. M., Paysan, J., Rino, J., Lopes, S., de Almeida, L. P., Cortes, L., & Nobre, R. J. (2022) · Gene Therapy · doi:10.1038/s41434-022-00372-z · Cited by 12
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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