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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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Citations
Cites
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“With the report in 2009 that AAV serotype 9 efficiently crosses the BBB following IV injection, a new era of CNS gene therapy began.(191) Additionally, an earlier study concluded that AAV9 vector genomes undergo axonal transport to distant neuron cell bodies.”
BackgroundLoss of mouse Stmn2 function causes motor neuropathy
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BackgroundMECP2 Isoform-Specific Vectors with Regulated Expression for Rett Syndrome Gene Therapy
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“Alternatively, the MeP promoter constructs could be delivered more broadly across the Blood Brain Barrier through the use of Adeno-Associated Virus 9 derived vectors [48].”
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“In neonatal mice (in which the BBB is not fully formed), a single facial vein injection of an AAV9 vector expressing green fluorescent protein (GFP) led to robust GFP expression in cells (predominantly motor neurons) throughout the brain and spinal cord [16].”
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BackgroundInfluentialIn Vivo Genome Editing as a Therapeutic Approach
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“A major challenge of the use of in vivo genome editing is the delivery of these therapeutic agents into the central nervous system (CNS).”
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“Intravascular administration of AAV9 (Foust et al., 2009) and intrathecal injections of AAV6 and AAV9 at the level of the lumbar spinal cord transduced SMN throughout the spinal cord (Snyder et al., 2011).”
BackgroundMacromolecular drug transport into the brain using targeted therapy
Lichota, J., Skjørringe, T., Thomsen, L. B., & Moos, T. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06544.x · Cited by 75
Adenoassociated virus serotype 9-mediated gene therapy for x-linked adrenoleukodystrophy
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An experimental platform for systemic drug delivery to the retina
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“In this regard, it is of note that adeno-associated virus (AAV) delivery systems have now been approved for use in a growing number of gene therapy trials, including those recently initiated for the congenital retinopathy Leber’s congenital amaurosis (38–40), and recent studies have indicated that AAV9 is capable of t…”
BackgroundSystemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1
Chandler, R. J., Williams, I. M., Gibson, A. L., Davidson, C. D., Incao, A. A., Hubbard, B. T., Porter, F. D., Pavan, W. J., & Venditti, C. P. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw367 · Cited by 74
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“Tissue De-targeting Compared with scAAV9wt-EGFP rAAV9 vectors transduced neurons more efficiently following IV delivery into neonatal mice than into adult mice.(7) Therefore, we next injected 4.”
BackgroundResultMattar, C. N. Z., Waddington, S. N., Biswas, A., Johana, N. B., Ng, X., Fisk, A. S., Fisk, N. M., Tan, L. G., Rahim, A. A., Buckley, S. M. K., et al. (2012) · Gene Therapy · doi:10.1038/gt.2011.216 · Cited by 69
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“Recently, adeno-associated virus (AAV) 9 injected intravenously has been shown to bypass the blood–brain barrier and efficiently target cells of the central nervous system (Foust et al. 2009).”
BackgroundBey, K., Ciron, C., Dubreil, L., Deniaud, J., Ledevin, M., Cristini, J., Blouin, V., Aubourg, P. R., & Colle, M.-A. (2017) · Gene Therapy · doi:10.1038/gt.2017.18 · Cited by 74
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Targeted delivery of miRNA therapeutics for cardiovascular diseases: opportunities and challenges
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“Gene replacement therapy for SMN protein is one of the most direct approaches to treat SMA patients, however the delivery issue has long been an obstacle, because the blood brain barrier (BBB) restricts delivery of therapeutics to the central nervous system (CNS), where an insufficiency of functional SMN has the most…”
BackgroundIntrapleural Administration of AAV9 Improves Neural and Cardiorespiratory Function in Pompe Disease
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Partial restoration of cardio-vascular defects in a rescued severe model of spinal muscular atrophy
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“This delivery mode allows distribution of the virus to the central nervous system as well as periphery organs, including heart [20,30].”
BackgroundImpaired Dendritic Development and Memory inSorbs2Knock-Out Mice
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Spinal muscular atrophy: An update on therapeutic progress
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Long non-coding RNAs in neurodevelopmental disorders
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“AAV9 vectors have the capacity to cross the blood-brain barrier and transduce neurons and astrocytes (Foust et al., 2009), making intravascular injection of viral vectors for CNS targeted gene therapy a possibility.”
BackgroundGenome engineering: a new approach to gene therapy for neuromuscular disorders
Nelson, C. E., Robinson-Hamm, J. N., & Gersbach, C. A. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.126 · Cited by 73
Scalable Production of AAV Vectors in Orbitally Shaken HEK293 Cells
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“scAAV9 cannot only deliver the SMN1 cDNA to muscle and other peripheral tissue, but also cross the BBB to reach the CNS and spinal motoneurons [92, 93, 195, 299].”
BackgroundOptogenetics in the nonhuman primate
Han, X. (2012) · Progress in brain research · doi:10.1016/b978-0-444-59426-6.00011-2 · Cited by 72
“However, intravenous delivery of AAV9 in adult mice almost exclusively transduces astrocytes throughout the entire CNS, with little neuronal transduction (Foust et al., 2009).”
Dufour, B. D., Smith, C. A., Clark, R. L., Walker, T. R., & McBride, J. L. (2014) · Molecular Therapy · doi:10.1038/mt.2013.289 · Cited by 71
Genetic therapy for the nervous system
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“This provides a range for the transduction efficiency which is in approximately the same range reported by other studies using different promoters [77,88].”
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“For example, intravenous injection of P1 mice with a scAAV9/ - actin-GFP construct led to a large population of transgene neurons and astrocytes (Foust et al., 2009).”
BackgroundResultInfluentialSelf-citationAAV gene delivery to the spinal cord: serotypes, methods, candidate diseases, and clinical trials
Hardcastle, N., Boulis, N. M., & Federici, T. (2017) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2018.1416089 · Cited by 70
“were pioneers in demonstrating that, following systemic administration, scAAV9 crossed the BBB without any pharmacological aid and successfully transduced the whole spinal cord [38,39].”
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“AAV9 can cross the blood-brain barrier (Figure 1).(23,24) The selfcomplementary feature of onasemnogene abeparvovec allows for rapid transgene expression.”
BackgroundParambi, D. G. T., Alharbi, K. S., Kumar, R., Harilal, S., Batiha, G. E., Martins, N. A., Hendawy, O. M., Musa, A., Panda, D. S., & Mathew, B. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02555-y · Cited by 76
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“25,26 Age-related differences in transduction have also been observed in NHPs.”
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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