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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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Citations
Cites
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BackgroundInfluentialPathways to Drug Development for Autism Spectrum Disorders
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“A major step toward the goal of systemic gene delivery to the CNS using AAV has been taken by Foust and colleagues”
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“Foust et al. (2009) discovered that AAV serotype 9, when delivered into the vasculature of neonatalmice, bypasses the blood–brain barrier and transduces a variety of neuronal populations and astrocytes throughout the spinal cord and brain.”
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“Serotype 9 was selected based on its ability to transduce a variety of neuronal lineages, including motor neurons (Duque et al., 2009; Foust et al., 2009).”
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“The ability of AAV serotype 9 (AAV9) to transduce neurons and glia in the CNS after an IV injection has raised new possibilities for global CNS delivery of therapeutic transgenes in rodents, cats, and nonhuman primates (Duque et al., 2009; Foust et al., 2009; Gray et al., 2011b).”
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Bone-Targeting AAV-Mediated Gene Silencing in Osteoclasts for Osteoporosis Therapy
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“In particular, rAAV9-mediated gene therapy is currently the leading platform for the treatment of neurological disorders,(38) as systemically delivered rAAV9 can traverse the blood-brain barrier to target the central nervous system (CNS).(39)”
BackgroundOverview of gene therapy in spinal muscular atrophy and Duchenne muscular dystrophy
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“robust transduction of brain and spinal cord neurons, including alpha motor neurons known to underlie the pathogenesis of SMA.(35) The engineering of a self‐complementary template allows the coding region of the recombinant virus to form an intramolecular double‐”
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“AAV9, after striatal injections displayed a neuronal, but not astrocytic or oligodendrocytic tropism, also previously reported for mice after striatal or cortical injections of AAV9 (Cearley and Wolfe, 2006; Foust et al. , 2009).”
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“More interestingly, rAAV9 has been shown to transduce neural tissue via retrograde transport after intramuscular delivery or even by crossing the blood–brain barrier itself (Foust et al., 2009; Bevan et al., 2011; Dayton et al., 2012; Dimattia et al., 2012; ElMallah et al., 2012).”
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“) injection of AAV9 has been proven to traverse the blood-brain barrier and efficiently transduce motor neurons in non-human primates.(4) As a result, AAV9 can serve as an effective vector for gene therapies for neurodegenerative diseases, as recently demonstrated in spinal muscular atrophy (SMA).”
BackgroundEthical Perspectives on Treatment Options with Spinal Muscular Atrophy Patients
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“Based on these considerations, and in keeping with translational goals, we elected the use of an intravascular approach, which is less invasive and made possible through the use of an AAV virus able to cross the BBB (Duque et al., 2009; Foust et al., 2009).”
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“AAV9 has been shown to cross the BBB and transduce large numbers of neurons and glia in rodents (Duque et al., 2009; Foust et al., 2009).”
Argininosuccinic aciduria fosters neuronal nitrosative stress reversed by Asl gene transfer
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“The dose of scAAV9 administered to humans, 2× 1014 vg/kg (10), is the same dose that causes a high incidence of delayed onset of hepatocellular carcinoma in mice (12).”
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“However, targeting of motor neurons was most effective following early postnatal administration 77 .”
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“Serotype 9 also holds greater promise as it has been shown to cross the blood–brain barrier in the absence of permeablizing reagents and it also preferentially transduces neurons and astrocytes [105,106].”
BackgroundGene and protein therapies utilizing VEGF for ALS
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“It also affords for intrathecal delivery of a VEGF-A gene therapy using the AAV-9 vector, which has the ability to cross the blood–brain barrier and transduce neural cells (Duque et al., 2009; Foust et al., 2009).”
Michelfelder, S., Varadi, K., Raupp, C., Hunger, A., Körbelin, J., Pahrmann, C., Schrepfer, S., Müller, O. J., Kleinschmidt, J. A., & Trepel, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023101 · Cited by 47
“AAV9 can even efficiently deliver genes to various cell-types of the central nervous system [8] and has the unique property to cross the blood-brain barrier (BBB) [9,10].”
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“B,(1) that achieves 40fold to 90-fold more efficient brain-wide transduction than the current standard, AAV9 (Figure 1d) [91].”
BackgroundMotor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis
Tosolini, A. P., & Sleigh, J. N. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00405 · Cited by 48
“Age-dependent differences in BBB permeability, neuropil density, and cell tropisms may contribute (Foust et al., 2009, 2010); however, the early temporal requirement for SMN has been corroborated using mice with inducible SMN alleles (Le et al., 2011; Lutz et al., 2011; Kariya et al., 2014a), and…”
BackgroundMethodInfluentialDelivering AAV to the Central Nervous and Sensory Systems
Peters, C. W., Maguire, C. A., & Hanlon, K. S. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.03.004 · Cited by 44
Cerebrospinal fluid flow extends to peripheral nerves further unifying the nervous system
Ligocki, A. P., Vinson, A. V., Yachnis, A. T., Dunn, W. A., Smith, D. E., Scott, E. A., Alvarez-Castanon, J. V., Montalvo, D. E. B., Frisone, O. G., Brown, G. A. J., et al. (2024) · Science Advances · doi:10.1126/sciadv.adn3259 · Cited by 48
“In contrast, adeno associated virus at 25 nm is usually excluded by the blood brain barrier (BBB)/blood nerve barrier (BNB) unless leakage is induced, or neurotropic selected sero types are used ( 30 – 32 ).”
Genetic approaches to study glial cells in the rodent brain
Pfrieger, F. W., & Ślęzak, M. (2011) · Glia · doi:10.1002/glia.22283 · Cited by 47
“This may be achieved by innate properties of viral particles or by including a cell-specific promoter in the viral construct (Colin et al., 2009; Foust et al., 2009).”
BackgroundRetrograde Gene Delivery to Hypoglossal Motoneurons Using Adeno-Associated Virus Serotype 9
ElMallah, M. K., Falk, D. J., Lane, M. A., Conlon, T. J., Lee, K., Shafi, N. I., Reier, P. J., Byrne, B. J., & Fuller, D. D. (2012) · Human Gene Therapy Methods · doi:10.1089/hgtb.2012.009 · Cited by 45
“Experimental observations from both humans (Hogan et al., 1969; DeRuisseau et al., 2009) and animal models (Lee et al., 2011; Qiu et al., 2012) are consistent with the concept that therapy targeting both skeletal muscle and the CNS may be required to fully correct motor deficits in Pompe.”
BackgroundInfluentialByrne, L. C., Lin, Y. J., Lee, T., Schaffer, D. V., & Flannery, J. G. (2014) · Molecular Therapy · doi:10.1038/mt.2014.181 · Cited by 45
Magnetic Nanoparticles Enhance Adenovirus Transduction In Vitro and In Vivo
Sapet, C., Pellegrino, C., Laurent, N., Sicard, F., & Zelphati, O. (2011) · Pharmaceutical Research · doi:10.1007/s11095-011-0629-9 · Cited by 45
Epigenetic Treatment of Neurological Disease
Gray, S. G. (2011) · Epigenomics · doi:10.2217/epi.11.67 · Cited by 45
Kline, R. A., Kaifer, K. A., Osman, E. Y., Carella, F., Tiberi, A., Ross, J., Pennetta, G., Lorson, C. L., & Murray, L. M. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006680 · Cited by 45
“AAV9 has a broad tropism for many tissues within the periphery and the central nervous system, including astrocytes and neuronal lineages [34].”
BackgroundStructural and cellular biology of adeno-associated virus attachment and entry
Zengel, J. R., & Carette, J. E. (2020) · Advances in virus research · doi:10.1016/bs.aivir.2020.01.002 · Cited by 47
Bodea, S., & Westmeyer, G. G. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.655247 · Cited by 45
Recombinant Adeno-Associated Virus Serotype 9 Gene Therapy in Spinal Muscular Atrophy
Kotulska, K., Fattal‐Valevski, A., & Haberlová, J. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.726468 · Cited by 45
“In preclinical study in mice it was shown that AAV9 virus, in contrast to AAV8 and AAV6, crossed the blood brain barrier and efficiently targeted cells of the central nervous system (44).”
BackgroundSaunders, N. R., Ek, C. J., & Dzięgielewska, K. M. (2009) · Nature Biotechnology · doi:10.1038/nbt0909-804 · Cited by 45
The curious case of AAV immunology
Keeler, A. M., Zhan, W., Ram, S., Fitzgerald, K. A., & Gao, G. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.03.037 · Cited by 49
Advances in the treatment of neuronal ceroid lipofuscinosis
Rosenberg, J. B., Chen, A., Kaminsky, S. M., Crystal, R. G., & Sondhi, D. (2019) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2019.1684258 · Cited by 41
Bucher, T., Colle, M.-A., Wakeling, E. N., Dubreil, L., Fyfe, J. C., Briot, D., Maquigneau, M., Raoul, S., Chérel, Y., Astord, S., et al. (2013) · Human Gene Therapy · doi:10.1089/hum.2012.218 · Cited by 44
“A promising alternative to target the MNs is the IV administration of AAV vectors, especially with AAV9 serotype (Duque et al., 2009; Foust et al., 2009, 2010; Valori et al., 2010; Bevan et al., 2011; Dominguez et al., 2011; Gray et al., 2011b).”
Spampanato, C., Leonibus, E. D., Dama, P., Gargiulo, A., Fraldi, A., Sorrentino, N. C., Russo, F., Nusco, E., Auricchio, A., Surace, E. M., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2010.299 · Cited by 47
Thomsen, G. M., Alkaslasi, M. R., Vit, J., Lawless, G., Godoy, M. I., Gowing, G., Shelest, O., & Svendsen, C. N. (2017) · Gene Therapy · doi:10.1038/gt.2017.9 · Cited by 46
Haenraets, K., Foster, E., Johannssen, H. C., Kandra, V., Frezel, N., Steffen, T., Jaramillo, V., Paterna, J., Zeilhofer, H. U., & Wildner, H. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14124 · Cited by 42
Intravenous rAAV2/9 injection for murine cochlear gene delivery
Shibata, S. B., Yoshimura, H., Ranum, P. T., Goodwin, A. T., & Smith, R. J. (2017) · Scientific Reports · doi:10.1038/s41598-017-09805-x · Cited by 44
Wang, W., Wen, D., Duan, W., Yin, J., Cui, C., Wang, Y., Li, Z., Liu, Y., & Li, C. (2018) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2018.02.015 · Cited by 44
How will the field of gene therapy survive its success?
Kaemmerer, W. F. (2018) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10090 · Cited by 45
“[31] Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK.”
BackgroundMacro roles for microRNAs in neurodegenerative diseases
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“Adeno-associated virus AAV9's ability of crossing the BBB after systemic administration opened new expectations for the development of gene therapy approaches for neurological disorders [76].”
BackgroundSuccessful Gene Therapy in Utero for Lethal Murine Hypophosphatasia
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Effective depletion of pre-existing anti-AAV antibodies requires broad immune targeting
Velazquez, V. M., Meadows, A. S., Pineda, R. J., Camboni, M., McCarty, D. M., & Fu, H. (2017) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2017.01.003 · Cited by 43
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The blood-brain barrier, a key bridge to treat neurodegenerative diseases
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Transverse sinus injections drive robust whole-brain expression of transgenes
Hamodi, A. S., Sabino, A. M., Fitzgerald, N. D., Moschou, D., & Crair, M. C. (2020) · eLife · doi:10.7554/elife.53639 · Cited by 43
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“…a wide variety of tissues in the body, including tissues of the CNS. AAV9 has also been shown to cross the blood brain barrier, which makes it particularly useful for systemic delivery with access to the brain (Duque et al., 2009; Foust et al., 2009; Gray et al., 2011; Zhang et al., 2011).”
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Translation of MicroRNA-Based Huntingtin-Lowering Therapies from Preclinical Studies to the Clinic
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“Most of the AAVs are not able to cross the BBB, with the exception of AAV9, which transduces the brain following intravenous injections.(117) The natural capacity of AAV9 to cross the BBB has been greatly augmented by further engineering the capsid, which led to a 40-fold and greater transduction in the murine brain w…”
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Systemic low‐molecular weight drug delivery to pre‐selected neuronal regions
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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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