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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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ResultClades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues
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MethodAdeno-associated virus serotype 8 efficiently delivers genes to muscle and heart
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Items 101–200 of 1,001
Strauss, K. A., Carson, V. J., Soltys, K. A., Young, M., Bowser, L. E., Puffenberger, E. G., Brigatti, K. W., Williams, K. B., Robinson, D. L., Hendrickson, C. L., et al. (2020) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2020.01.006 · Cited by 161
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Impact of microRNAs on ischemic stroke: From pre- to post-disease
Li, G., Morris-Blanco, K. C., Lopez, M. S., Yang, T., Zhao, H., Vemuganti, R., & Luo, Y. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.08.002 · Cited by 159
“adeno-associated virus (AAV) vector is a way to cross the BBB, and recombinant AAV9 capsid effectively passes through the BBB (Foust et al., 2009).”
BackgroundSpinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment
Nishio, H., Niba, E. T. E., Saito, T., Okamoto, K., Takeshima, Y., & Awano, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241511939 · Cited by 183
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Murlidharan, G., Samulski, R. J., & Asokan, A. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00076 · Cited by 173
“…to perform extensive neuronal and glial transduction from different routes of injection in small and large animal models (Cearley and Wolfe, 2007; Foust et al., 2009; Bevan et al., 2011; Dayton et al., 2012; Ahmed et al., 2013; Benkhelifa-Ziyyat et al., 2013; Iwata et al., 2013; Yamashita et…”
MethodSamaranch, L., Sebastian, W. S., Kells, A. P., Salegio, E. A., Heller, G., Bringas, J. R., Pivirotto, P., DeArmond, S., Forsayeth, J., & Bankiewicz, K. S. (2014) · Molecular Therapy · doi:10.1038/mt.2013.266 · Cited by 142
György, B., Fitzpatrick, Z., Crommentuijn, M. H. W., Mu, D., & Maguire, C. A. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.05.032 · Cited by 153
“We chose to use the AAV9 serotype for our studies as it is able to cross the BBB and efficiently transduce cells in the brain [38], our target organ.”
MethodComparison of Adeno-Associated Viral Vector Serotypes for Spinal Cord and Motor Neuron Gene Delivery
Snyder, B. R., Gray, S. J., Quach, E. T., Huang, J. W., Leung, C. H., Samulski, R. J., Boulis, N. M., & Federici, T. (2011) · Human Gene Therapy · doi:10.1089/hum.2011.008 · Cited by 156
“Of note, two different promoters were used in these studies: the Cba promoter was used in the first study (Foust et al. , 2009) and the CMV promoter was used in the latter (Duque et al. , 2009).”
Samaranch, L., Salegio, E. A., Sebastián, W. S., Kells, A. P., Bringas, J. R., Forsayeth, J., & Bankiewicz, K. S. (2013) · Human Gene Therapy · doi:10.1089/hum.2013.005 · Cited by 158
“The primary reason for this interest is that AAV9 shows a remarkable ability to breach the blood–brain barrier after intravenous injection (Foust et al., 2008; Foust and Kaspar, 2009; Gray et al., 2011; Samaranch et al., 2012), and it also seems to be relatively efficient in transducing various…”
BackgroundCastle, M. J., Gershenson, Z. T., Giles, A. R., Holzbaur, E. L. F., & Wolfe, J. H. N. (2014) · Human Gene Therapy · doi:10.1089/hum.2013.189 · Cited by 165
“…2006), diffusely transduce large brain volumes via intraventricular (Passini et al. , 2003; Karolewski and Wolfe, 2006; Cearley et al. , 2008) or intravenous administration (Foust et al. , 2009; Gray et al. , 2011), or transfer genes to primary cultures of neurons and glia (Royo et al. , 2008).”
Adeno-associated virus (AAV) gene therapy for neurological disease
Weinberg, M. S., Samulski, R. J., & McCown, T. J. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.03.004 · Cited by 161
“The discovery that self-complementary (sc)AAV9 readily crosses the bloodebrain barrier to transduce brain and spinal neurons (Foust et al., 2008) has raised the possibility of gene therapy for non-focal neurological disorders.”
BackgroundNoninvasive, Transient and Selective Blood-Brain Barrier Opening in Non-Human Primates In Vivo
Marquet, F., Tung, Y., Teichert, T., Ferrera, V. P., & Konofagou, E. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022598 · Cited by 152
“Even the latest advances in brain gene therapy [4] provide cell specific drug delivery but are not region specific.”
BackgroundLiguore, W. A., Domire, J. S., Button, D. A., Wang, Y., Dufour, B. D., Srinivasan, S., & McBride, J. L. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.07.017 · Cited by 157
“Although global CNS gene delivery has made significant progress in the last decade, the transduction efficiency of AAVs that cross the BBB and target widespread regions of the brain still remains quite low in comparison with transduction efficiencies achieved from direct brain injections.(22,40) New AAV capsid mutants…”
BackgroundRett Syndrome: Crossing the Threshold to Clinical Translation
Katz, D. M., Bird, A., Coenraads, M., Gray, S. J., Menon, D. U., Philpot, B. D., & Tarquinio, D. C. (2016) · Trends in Neurosciences · doi:10.1016/j.tins.2015.12.008 · Cited by 150
“The recent discovery of adeno-associated virus (AAV) vector designs, such as AAV9, that can achieve widespread gene transfer across the nervous system has opened up the possibility of a translatable gene therapy approach for RTT [52–54].”
BackgroundAdachi, K., Enoki, T., Kawano, Y., Veraz, M., & Nakai, H. (2014) · Nature Communications · doi:10.1038/ncomms4075 · Cited by 152
Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids
Castle, M. J., Turunen, H. T., Vandenberghe, L. H., & Wolfe, J. H. (2016) · Methods in Molecular Biology · doi:10.1007/978-1-4939-3271-9_10 · Cited by 151
Noninvasive and targeted delivery of therapeutics to the brain using focused ultrasound
Poon, C., McMahon, D., & Hynynen, K. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.02.014 · Cited by 150
“Intravenous injection of adeno-associated virus-9 (AAV9) has been shown to target various cell populations of the CNSwithout BBBO (Foust et al., 2009).”
Adeno-Associated Virus Toolkit to Target Diverse Brain Cells
Challis, R. C., Ravindra Kumar, S., Chen, X., Goertsen, D., Coughlin, G. M., Hori, A. M., Chuapoco, M. R., Otis, T. S., Miles, T. F., & Gradinaru, V. (2022) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-111020-100834 · Cited by 148
“Several variables,including age (Chakrabarty et al.2013,Foust et al.2009),sex (Maguire et al. 2013), strain (He et al. 2019, Hordeaux et al. 2018), and species (Hordeaux et al. 2018, Matsuzaki et al. 2018, Watakabe et al. 2015), can affect AAV brain transduction.”
BackgroundExosome-associated AAV vector as a robust and convenient neuroscience tool
Hudry, E., Martin, C., Gandhi, S., György, B., Scheffer, D. I., Mu, D., Merkel, S. F., Mingozzi, F., Fitzpatrick, Z., Dimant, H., et al. (2016) · Gene Therapy · doi:10.1038/gt.2016.11 · Cited by 146
“Data presented in previous studies suggest that both EVs and AAV alone can traverse the blood-brain barrier (BBB) after intravascular administration (7, 8, 30, 31).”
The advent of AAV9 expands applications for brain and spinal cord gene delivery
Dayton, R. D., Wang, D. B., & Klein, R. L. (2012) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2012.681463 · Cited by 144
Song, S., Miranda, C. J., Braun, L., Meyer, K., Frakes, A. E., Ferraiuolo, L., Likhite, S. B., Bevan, A. K., Foust, K. D., McConnell, M. J., et al. (2016) · Nature Medicine · doi:10.1038/nm.4052 · Cited by 153
Self-citationRecent progress and considerations for AAV gene therapies targeting the central nervous system
Lykken, E. A., Shyng, C., Edwards, R. J., Rozenberg, A. J., & Gray, S. J. (2018) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-018-9234-0 · Cited by 144
“In the last decade, a third-generation vector, AAV9, was determined to have a wide distribution in the brain and spinal cord, targeting both neurons and astrocytes [10, 16].”
BackgroundTargeting microglia with lentivirus and AAV: Recent advances and remaining challenges
Maes, M. E., Colombo, G., Schulz, R., & Siegert, S. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134310 · Cited by 145
“Only a few studies describe minimal microglial transduction without further quantification [41,61].”
Haney, M. J., Zhao, Y., Harrison, E. B., Mahajan, V., Ahmed, S., He, Z., Suresh, P., Hingtgen, S., Klyachko, N. L., Mosley, R. L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061852 · Cited by 144
“Although certain types of AAV are more efficient at transducting the brain [60], wide variation among serotypes is observed”
BackgroundRetractedAdeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System
Zacchigna, S., Zentilin, L., & Giacca, M. (2014) · Circulation Research · doi:10.1161/circresaha.114.302331 · Cited by 144
Immunogenicity of CRISPR therapeutics—Critical considerations for clinical translation
Ewaisha, R., & Anderson, K. S. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1138596 · Cited by 153
“Tailored tropism of the viral vector is another strategy that could circumvent the blood brain barrier (Cearley et al., 2008; Foust et al., 2009), although an immune response to these vectors or to the gene editing components that they carry is not precluded.”
BackgroundSimultaneous mesoscopic and two-photon imaging of neuronal activity in cortical circuits
Barson, D. G., Hamodi, A. S., Shen, X., Lür, G., Constable, R. T., Cardin, J. A., Crair, M. C., & Higley, M. J. (2019) · Nature Methods · doi:10.1038/s41592-019-0625-2 · Cited by 135
“AAV9 crosses the blood-brain barrier 37 , and recently published work demonstrated whole-brain gene delivery by retro-orbital injection of this serotype as well as other engineered AAV variants 38 .”
Base editing rescue of spinal muscular atrophy in cells and in mice
Arbab, M., Matuszek, Ż., Kray, K. M., Du, A., Newby, G. A., Blatnik, A. J., Raguram, A., Richter, M. F., Zhao, K. T., Levy, J. M., et al. (2023) · Science · doi:10.1126/science.adg6518 · Cited by 144
Bone-targeting AAV-mediated silencing of Schnurri-3 prevents bone loss in osteoporosis
Yang, Y.-S., Xie, J., Wang, D., Kim, J., Tai, P. W. L., Gravallese, E. M., Gao, G., & Shim, J. (2019) · Nature Communications · doi:10.1038/s41467-019-10809-6 · Cited by 149
Spinal muscular atrophy—recent therapeutic advances for an old challenge
Faravelli, I., Nizzardo, M., Comi, G. P., & Corti, S. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.77 · Cited by 138
Identification of the Galactose Binding Domain of the Adeno-Associated Virus Serotype 9 Capsid
Bell, C. L., Gurda, B. L., Vliet, K. V., Agbandje‐McKenna, M., & Wilson, J. M. (2012) · Journal of Virology · doi:10.1128/jvi.00448-12 · Cited by 142
“For example, after intravenous injection, AAV9 can surpass the blood-brain barrier and transduce motor neurons in the spinal cord of adult and neonatal mice and cats, as well as neurons in the neonatal mouse brain and astrocytes in the adult mouse brain (9, 11).”
BackgroundGenetics and Therapies for GM2 Gangliosidosis
Cachón-González, M. B., Zaccariotto, E., & Cox, T. M. (2018) · Current Gene Therapy · doi:10.2174/1566523218666180404162622 · Cited by 141
“Furthermore, when they intracranially injected 4-month old TSD mice with selfcomplementary AAV9 (scAAV9) expressing HEXM, there was a reduction in brain ganglioside and its clearance was comparable to outcomes observed in animals injected with scAAV9 expressing HEXA.”
InfluentialMerkel, S. F., Andrews, A. M., Lutton, E. M., Mu, D., Hudry, E., Hyman, B. T., Maguire, C. A., & Ramirez, S. H. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13861 · Cited by 132
AAV vectors applied to the treatment of CNS disorders: Clinical status and challenges
Kang, L., Jin, S., Wang, J., Lv, Z., Xin, C., Tan, C., Zhao, M., Wang, L., & Liu, J. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.01.067 · Cited by 131
Thomsen, G. M., Gowing, G., Latter, J., Chen, M., Vit, J., Staggenborg, K., Avalos, P., Alkaslasi, M. R., Ferraiuolo, L., Likhite, S. B., et al. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2037-14.2014 · Cited by 137
“The shRNA to mutant SOD1 was fused to the GFP reporter, and both genes were packaged in AAV9, known to infect neurons (Foust et al., 2009).”
MethodInfluentialSelf-citationHsu, P.-H., Wei, K.-C., Huang, C.-Y., Wen, C.-J., Yen, T.-C., Liu, C.-L., Lin, Y.-T., Chen, J.-C., Shen, C.-R., & Liu, H.-L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057682 · Cited by 136
“This finding suggests that systemic administration of viral vector for CNS transduction could be achieved without viral toxicity, as opposed to other reports of viral IV administration that required much higher concentrations (10-10 vg/ml [20,21,22]).”
ResultAdeno-Associated Virus Vectors and Neurological Gene Therapy
Ojala, D. S., Amara, D. P., & Schaffer, D. V. (2014) · The Neuroscientist · doi:10.1177/1073858414521870 · Cited by 143
Adeno-Associated Viral Vectors and Their Redirection to Cell-Type Specific Receptors
Michelfelder, S., & Trepel, M. (2009) · Advances in genetics · doi:10.1016/s0065-2660(09)67002-4 · Cited by 138
Astrogliosis in Amyotrophic Lateral Sclerosis: Role and Therapeutic Potential of Astrocytes
Vargas, M. R., & Johnson, J. A. (2010) · Neurotherapeutics · doi:10.1016/j.nurt.2010.05.012 · Cited by 145
“Interestingly, it might be possible to specifically target astrocytes in adult mice by intravenous injection of specific adenoassociated virus serotypes.(147) The chemical comVARGAS AND JOHNSON 477”
BackgroundGlial promoter selectivity following AAV-delivery to the immature brain
von Jonquieres, G., Mersmann, N., Klugmann, C. B., Harasta, A. E., Lutz, B., Teahan, O., Housley, G. D., Fröhlich, D., Krämer-Albers, E.-M., & Klugmann, M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065646 · Cited by 133
“This developmental stage of the mouse CNS translates to the start of the last prenatal trimester in humans [32].”
BackgroundInfluentialEngineered AAVs for non-invasive gene delivery to rodent and non-human primate nervous systems
Chen, X., Kumar, S. R., Adams, C. D., Yang, D., Wang, T., Wolfe, D. A., Arokiaraj, C. M., Ngo, V., Campos, L., Griffiths, J. A., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.05.003 · Cited by 138
“IV-delivered AAV-MaCPNS1/2 transduces the infant rhesus macaque CNS and PNS more efficiently than AAV9 Encouraged by the tropism of MaCPNS1/2 capsids in marmosets, we further assessed their transduction potential in another NHP, the rhesus macaque, an Old World monkey, and a common pre-clinical research model for AAV…”
BackgroundInfluentialDodge, J. C., Treleaven, C. M., Fidler, J. A., Hester, M. E., Haidet, A. M., Handy, C. R., Rao, M., Eagle, A., Cowger, J. A., Taksir, T. V., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.206 · Cited by 130
Self-citationTemporal requirement for high SMN expression in SMA mice
Le, T. T., McGovern, V. L., Alwine, I. E., Wang, X., Massoni‐Laporte, A., Rich, M. M., & Burghes, A. H. M. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr275 · Cited by 130
“When high-titer virus is used, scAAV9 crosses the blood–brain barrier resulting in considerable transduction of motor neurons and rescue of SMN △7 SMA mice beyond a year of age (52,55,56,73,74).”
BackgroundGene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes
Waldrop, M. A., Karingada, C., Storey, M. A., Powers, B. R., Iammarino, M. A., Miller, N. F., Alfano, L. N., Noritz, G. H., Rossman, I. T., Ginsberg, M., et al. (2020) · PEDIATRICS · doi:10.1542/peds.2020-0729 · Cited by 134
Benkhelifa‐Ziyyat, S., Besse, A., Roda, M., Duqué, S. I., Astord, S., Carcenac, R., Marais, T., & Barkats, M. (2013) · Molecular Therapy · doi:10.1038/mt.2012.261 · Cited by 128
New treatments in spinal muscular atrophy: an overview of currently available data
Ramdas, S., & Servais, L. (2020) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2019.1704732 · Cited by 132
“The adenovirus can cross the blood-brain barrier and enters motor neurons in the central nervous system after intravenous injection [46].”
BackgroundGene therapy for neurodegenerative diseases
O’Connor, D. M., & Boulis, N. M. (2015) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2015.06.001 · Cited by 135
Seung Taik, L. I. M., Airavaara, M., & Harvey, B. K. (2009) · Pharmacological Research · doi:10.1016/j.phrs.2009.10.002 · Cited by 128
The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy
Sleigh, J. N., Gillingwater, T. H., & Talbot, K. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.007245 · Cited by 126
“This could be explained either by a higher level of motor neuron transduction efficiency in P1 mice compared with older mice (Foust et al., 2009) or by the effect of increased Smn levels being heavily dependent on the stage of development.”
Current clinical applications of AAV-mediated gene therapy
Byrne, B. J., Flanigan, K. M., Matesanz, S. E., Finkel, R. S., Waldrop, M. A., D'Ambrosio, E. S., Johnson, N. E., Smith, B. K., Bönnemann, C. G., Carrig, S., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.04.045 · Cited by 152
Morabito, G., Giannelli, S. G., Ordazzo, G., Bido, S., Castoldi, V., Indrigo, M. T., Cabassi, T., Cattaneo, S., Luoni, M., Cancellieri, C., et al. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2017.08.004 · Cited by 128
“However, the same approach results in a lower transduction efficiency by the AAV9 in adult mice, with increased targeting of the glial cells with respect to the neuronal fraction.(5,7,9) Thus, recent research has focused on generating novel AAV9 variants through selected mutagenesis of the capsid proteins to obtain mo…”
BackgroundAstrocytes influence the severity of spinal muscular atrophy
Rindt, H., Feng, Z., Mazzasette, C., Glascock, J., Valdivia, D. O., Pyles, N. J., Crawford, T. O., Swoboda, K. J., Patitucci, T. N., Ebert, A. D., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv148 · Cited by 123
“AAV9 crosses the incompletely formed blood–brain barrier in newborn mice and effectively transduces cells of the central nervous system (CNS), including astrocytes (13).”
Yue, Y., Pan, X., Hakim, C. H., Kodippili, K., Zhang, K., Shin, J., Yang, H. T., McDonald, T., & Duan, D. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv310 · Cited by 126
Viral Vectors and Delivery Strategies for CNS Gene Therapy
Gray, S. J., Woodard, K., & Samulski, R. J. (2010) · Therapeutic Delivery · doi:10.4155/tde.10.50 · Cited by 130
Puls, B., Ding, Y. P., Zhang, F., Pan, M., Lei, Z., Pei, Z., Jiang, M. H., Bai, Y., Forsyth, C., Metzger, M., et al. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.591883 · Cited by 124
“Reactive astrogliosis is common to CNS injury, and particularly severe after SCI. Resident astrocytes react to injuryinduced cytokines and dramatically upregulate the expression of a number of proteins such as the astrocytic marker GFAP and the neural progenitor markers Nestin and Vimentin (Sofroniew, 2009).”
BackgroundInfluentialChang, Q., Wang, J., Li, Q., Kim, Y., Zhou, B., Wang, Y., Li, H., & Lin, X. (2015) · EMBO Molecular Medicine · doi:10.15252/emmm.201404929 · Cited by 119
“Recent advances in developing new viral vehicles aimed at effectively penetrating the blood – brain barrier (Foust et al , 2009; Manfredsson et al , 2009) or diffusing across dense tissue for gene delivery in the eyes (Dalkara et al , 2013) are promising candidates for further examining whether…”
Adeno-Associated Viral Vectors in Neuroscience Research
Haggerty, D. L., Grecco, G. G., Reeves, K. C., & Atwood, B. K. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.11.012 · Cited by 135
“S can target neurons in the CNS and PNS, respectively, when injected intravenously, bypassing the need to perform site-directed injections in the brain,23,48,49 but also see Foust et al.27 This approach decreases experimental complexity for research paradigms and also opens new avenues to targeting neurons for therape…”
BackgroundBey, K., Deniaud, J., Dubreil, L., Joussemet, B., Cristini, J., Ciron, C., Hordeaux, J., Boulc’h, M. L., Marche, K., Maquigneau, M., et al. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.04.001 · Cited by 115
“In mice and large animal models, AAV9 was able to bypass the blood-brain barrier (BBB) and target predominantly neurons and spinal motor neurons (MNs), especially when the vector was administered intravenously at an early stage of life.(1,2) These AAV9 properties show spectacular outcomes in animal models(3,4) and cli…”
Viral Vectors for Neural Circuit Mapping and Recent Advances in Trans-synaptic Anterograde Tracers
Xu, X., Holmes, T. C., Luo, M., Beier, K. T., Horwitz, G. D., Zhao, F., Zeng, W., Hui, M., Semler, B. L., & Sandri-Goldin, R. M. (2020) · Neuron · doi:10.1016/j.neuron.2020.07.010 · Cited by 126
Yao, Y., Wang, J., Liu, Y., Qu, Y., Wang, K., Zhang, Y., Chang, Y., Yang, Z., Wan, J., Liu, J., et al. (2022) · Nature Biomedical Engineering · doi:10.1038/s41551-022-00938-7 · Cited by 120
Murray, L. M., Lee, S., Bäumer, D., Parson, S. H., Talbot, K., & Gillingwater, T. H. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp506 · Cited by 116
Biodistribution of onasemnogene abeparvovec DNA, mRNA and SMN protein in human tissue
Thomsen, G. M., Burghes, A. H. M., Hsieh, C., Do, J., Chu, B. T. T., Perry, S., Barkho, B. Z., Kaufmann, P., Sproule, D. M., Feltner, D. E., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01483-7 · Cited by 114
Self-citationPerez, B. A., Shutterly, A., Chan, Y. K., Byrne, B. J., & Corti, M. (2020) · Brain Sciences · doi:10.3390/brainsci10020119 · Cited by 112
“Of the common capsids currently available, AAV9 has emerged as the most widely used for CNS gene therapy applications due to its enhanced spread across CNS structures and its ability to penetrate the BBB even after peripheral administration in neonatal animals [61,62].”
BackgroundIn Vivo Selection Yields AAV-B1 Capsid for Central Nervous System and Muscle Gene Therapy
Choudhury, S., Fitzpatrick, Z., Harris, A. F., Maitland, S. A., Ferreira, J. S., Zhang, Y., Ma, S., Sharma, R. B., Gray‐Edwards, H. L., Johnson, J. A., et al. (2016) · Molecular Therapy · doi:10.1038/mt.2016.84 · Cited by 118
MicroRNAs Expression and Function in Cerebral Ischemia Reperfusion Injury
Yu, D., Yang, L., Feng, Y., Fan, C., Wang, S., & Mo, X. (2014) · Journal of Molecular Neuroscience · doi:10.1007/s12031-014-0293-8 · Cited by 113
Tordo, J., O’Leary, C., Antunes, A. S. L. M., Palomar, N., Aldrin-Kirk, P., Basche, M., Bennett, A., D’Souza, Z., Gleitz, H., Godwin, A., et al. (2018) · Brain · doi:10.1093/brain/awy126 · Cited by 113
“These include the discovery of new AAV serotypes in humans and non-human primates and the thorough characterization of their brain tropism (Gao et al., 2002, 2004; Cearley and Wolfe, 2006; Foust et al., 2009; Bevan et al., 2011).”
Choudhury, S., Harris, A. F., Cabral, D. J., Keeler, A. M., Sapp, E., Ferreira, J. S., Gray‐Edwards, H. L., Johnson, J. A., Johnson, A. K., Su, Q., et al. (2015) · Molecular Therapy · doi:10.1038/mt.2015.231 · Cited by 116
Treating Rett syndrome: from mouse models to human therapies
Vashi, N., & Justice, M. J. (2019) · Mammalian Genome · doi:10.1007/s00335-019-09793-5 · Cited by 116
A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna
Taghian, T., Marosfoi, M. G., Puri, A. S., Cataltepe, O. I., King, R. M., Diffie, E. B., Maguire, A. S., Martin, D. R., Fernau, D., Batista, A. R., et al. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.11.012 · Cited by 111
“The GFP vector, scAAV-CB-GFP, consisted of an AAV serotype 9 capsid carrying an expression cassette comprising a version of the chicken b-actin promoter, a GFP cDNA, and an artificial intron.(16) The GFP vector was produced by triple transfection as previously described and purified by cesium chloride gradient.”
MethodCiesielska, A., Hadaczek, P., Mittermeyer, G., Zhou, S., Wright, J. F., Bankiewicz, K. S., & Forsayeth, J. (2013) · Molecular Therapy · doi:10.1038/mt.2012.167 · Cited by 108
McLean, J. R., Smith, G. A., Rocha, E. M., Hayes, M. A., Beagan, J. A., Hallett, P. J., & Ole Isacson, A. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.05.044 · Cited by 112
Abati, E., Bresolin, N., Comi, G. P., & Corti, S. P. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1738390 · Cited by 107
“cords of newborn mice but scarce distribution mostly limited to astrocytes in adult mice [92].”
BackgroundMethods for Gene Transfer to the Central Nervous System
Kantor, B., Bailey, R. M., Wimberly, K., Kalburgi, S. N., & Gray, S. J. (2014) · Advances in Genetics · doi:10.1016/b978-0-12-800149-3.00003-2 · Cited by 109
“Work by Duque et al. (2009) and Foust et al. (2009) demonstrated that AAV9 crosses the BBB in mice and cats when injected intravenously in both neonatal and adult animals; AAV8 was also found to cross the BBB in mice, although to a lesser extent than AAV9 (Gray, Matagne, et al., 2011).”
BackgroundClinical Gene Therapy for Neurodegenerative Diseases: Past, Present, and Future
Piguet, F., Alves, S., & Cartier, N. (2017) · Human Gene Therapy · doi:10.1089/hum.2017.160 · Cited by 115
“neuronal transduction, whereas adult delivery led mostly to astrocyte transduction.(15) AAVs with modified capsids that were engineered to cross the BBB are being continuously optimized to reach the foremost regions of the CNS with less-invasive routes of administration relative to intracranial injections, a promising…”
Weisenburger, S., & Vaziri, A. (2018) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-072116-031458 · Cited by 110
“…through e.g. lentiand adeno-associated viruses (Dittgen et al. 2004, Tian et al. 2009) including systemic delivery approaches (Chan et al. 2017, Foust et al. 2008, Shimogori & Ogawa 2008), as well as methods for genomic integration of the transgenes and generation of transgenic animals (Ji et…”
Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease
Rafi, M. A., Rao, H. Z., Luzi, P., Curtis, M. T., & Wenger, D. A. (2012) · Molecular Therapy · doi:10.1038/mt.2012.153 · Cited by 108
NEUROD1 Instructs Neuronal Conversion in Non-Reactive Astrocytes
Brulet, R., Matsuda, T., Zhang, L., Miranda, C. J., Giacca, M., Kaspar, B. K., Nakashima, K., & Hsieh, J. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.04.013 · Cited by 111
“Previouswork suggests that intravascular delivery ofAAV9 is an ideal tool for targeting astrocytes in certain brain regions (Foust et al., 2009).”
BackgroundMethodInfluentialSelf-citationO’Carroll, S. J., Cook, W. H., & Young, D. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.618020 · Cited by 112
“Glial transduction was more robust in adult animals, while transduction in neonatal animals was primarily neuronal (Foust et al., 2009; Gray et al., 2011; Yang et al., 2014).”
BackgroundGlobal brain delivery of neprilysin gene by intravascular administration of AAV vector in mice
Iwata, N., Sekiguchi, M., Hattori, Y., Takahashi, A., Asai, M., Ji, B., Higuchi, M., Staufenbiel, M., Muramatsu, S., & Saido, T. C. (2013) · Scientific Reports · doi:10.1038/srep01472 · Cited by 108
Nanobody-Enhanced Targeting of AAV Gene Therapy Vectors
Eichhoff, A. M., Börner, K., Albrecht, B., Schäfer, W., Baum, N., Haag, F., Körbelin, J., Trepel, M., Braren, I., Grimm, D., et al. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.09.003 · Cited by 118
Stoica, L., Todeasa, S. H., Cabrera, G. T., Salameh, J. S., ElMallah, M. K., Mueller, C., Brown, R. H., & Sena‐Esteves, M. (2016) · Annals of Neurology · doi:10.1002/ana.24618 · Cited by 107
“The latest generation of AAV vectors based on AAV9 and AAVrh10 capsids transduces multiple cell types in the spinal cord, including motor neurons, at high efficiency.(18,19) This broad tropism in the spinal cord is especially important, as misfolded hSOD1 is ubiquitously expressed (neurons, astrocytes, microglia, olig…”
BackgroundStanimirovic, D. B., Sandhu, J. K., & Costain, W. J. (2018) · BioDrugs · doi:10.1007/s40259-018-0309-y · Cited by 109
Huang, W., Liu, X., Cao, J., Meng, F., Li, M., Chen, B., & Zhang, J. (2014) · Journal of Molecular Neuroscience · doi:10.1007/s12031-014-0434-0 · Cited by 105
“Recombinant AAV for gene delivery has been reported to be capable of passing through the blood brain barrier, which has been implied as a promising vehicle for gene therapy (Foust et al. 2009).”
Weismann, C. M., Ferreira, J. S., Keeler, A. M., Su, Q., Qui, L., Shaffer, S. A., Xu, Z., Gao, G., & Sena‐Esteves, M. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv168 · Cited by 102
“AAV9 vectors are capable of crossing the blood–brain barrier (BBB) after intravascular delivery and achieve widespread transduction of neurons and glia in neonatal (25) and adult animals (25,26).”
BackgroundRuzo, A., Marcó, S., García, M., Villacampa, P., Ribera, A., Ayuso, E., Maggioni, L., Mingozzi, F., Haurigot, V., & Bosch, F. (2012) · Human Gene Therapy · doi:10.1089/hum.2012.029 · Cited by 108
“…virus 9 (AAV9), a recently isolated AAV serotype (Gao et al. , 2004), can cross the BBB from the bloodstream and transduce neurons and astrocytes in multiple brain areas, while also transducing the liver and heart very efficiently (Duque et al. , 2009; Foust et al. , 2009; Gray et al. , 2011).”
Tanguy, Y., Biferi, M. G., Besse, A., Astord, S., Cohen-Tannoudji, M., Marais, T., & Barkats, M. (2015) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00036 · Cited by 103
“…in both adult (Barkats, 2007; Duqué et al., 2009; Benkhelifa-Ziyyat et al., 2013) and neonatal animals (Barkats, 2007; Duqué et al., 2009; Foust et al., 2009; Benkhelifa-Ziyyat et al., 2013), including large animals such as cats (Barkats, 2007; Duqué et al., 2009) and NHPs (Bevan et al.,…”
BackgroundPharmacosynthetics: Reimagining the pharmacogenetic approach
Farrell, M. S., & Roth, B. L. (2012) · Brain Research · doi:10.1016/j.brainres.2012.09.043 · Cited by 103
Systemic delivery of adeno-associated viral vectors
Duan, D. (2016) · Current Opinion in Virology · doi:10.1016/j.coviro.2016.07.006 · Cited by 105
RNAi: a potential new class of therapeutic for human genetic disease
Seyhan, A. A. (2011) · Human Genetics · doi:10.1007/s00439-011-0995-8 · Cited by 104
MeCP2 and Rett syndrome: reversibility and potential avenues for therapy
Gadalla, K. K. E., Bailey, M. E. S., & Cobb, S. (2011) · Biochemical Journal · doi:10.1042/bj20110648 · Cited by 101
Batista, A. R., King, O. D., Reardon, C. P., Davis, C., Shankaracharya, Philip, V. M., Gray‐Edwards, H. L., D, N. A. M., Lutz, C. M., Landers, J. E., et al. (2019) · Human Gene Therapy · doi:10.1089/hum.2019.186 · Cited by 97
“The discovery that AAV9 crosses the blood– brain barrier (BBB) after systemic administration in mice 3 started a new era of intravascular gene therapy for CNS diseases.”
Ahmed, S. S., Li, H., Cao, C., Şıkoğlu, E. M., Denninger, A. R., Su, Q., Eaton, S. C., Navarro, A. A. L., Xie, J., Szucs, S., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.138 · Cited by 97
Rahim, A. A., Wong, A. M. S., Hoefer, K., Buckley, S. M. K., Mattar, C. N. Z., Cheng, S. H., Chan, J. K. Y., Cooper, J. D., & Waddington, S. N. (2011) · The FASEB Journal · doi:10.1096/fj.11-182311 · Cited by 101
“The decision to use AAV2/9 in this study was based on the recent interest and subsequent above-mentioned studies that confirmed its ability to cross the BBB in neonatal and adult animal models (5, 6).”
MethodGene Therapy for ALS—A Perspective
Cappella, M., Ciotti, C., Cohen-Tannoudji, M., & Biferi, M. G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184388 · Cited by 103
“A breakthrough in the treatment of MNDs emerged with the finding that sc viral vectors, derived from AAV9 cross the blood brain barrier in animal models [107,116].”
BackgroundGene therapy for CNS disorders: modalities, delivery and translational challenges
Gao, J., Gunasekar, S., Xia, Z. J., Shalin, K., Jiang, C., Chen, H., Lee, D., Lee, S., Pisal, N. D., Luo, J. N., et al. (2024) · Nature reviews. Neuroscience · doi:10.1038/s41583-024-00829-7 · Cited by 100
“Although AAV9 was the first serotype to display significant brain transduction after intravenous administration 123,124 , both AAVrh8 and AAVrh10 were subsequently shown to be just as effective as AAV9.”
Gene Therapy for the Nervous System: Challenges and New Strategies
Maguire, C. A., Ramirez, S. H., Merkel, S. F., Sena‐Esteves, M., & Breakefield, X. O. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0299-5 · Cited by 99
“[21] reported that AAV serotype 9 (AAV9) vectors could cross the intact BBB in neonates and adult mice and yield “widespread” transgene expression in astrocytes, neurons, and endothelial cells.”
BackgroundInfluentialTRIM11 protects against tauopathies and is down-regulated in Alzheimer’s disease
Zhang, Z., Harischandra, D. S., Wang, R., Ghaisas, S., Zhao, J. Y., McMonagle, T. P., Zhu, G., Lacuarta, K. D., Song, J., Trojanowski, J. Q., et al. (2023) · Science · doi:10.1126/science.add6696 · Cited by 95
“To evaluate the effect of TRIM11 up-regulation, we clonedTRIM11 and, as a control, GFP into the adeno-associated virus AAV9 vector, a serotype that effectively targets cells in the central nervous system (64) (fig.”
MethodThe Role of Cell-Penetrating Peptide and Transferrin on Enhanced Delivery of Drug to Brain
Sharma, G., Lakkadwala, S., Modgil, A., & Singh, J. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17060806 · Cited by 95
“Viruses are equipped with different molecular mechanisms to overcome these hurdles and can, therefore, serve as efficient delivery vectors [38].”
RNA-targeted splice-correction therapy for neuromuscular disease
Wood, M. J. A., Gait, M. J., & Yin, H. (2010) · Brain · doi:10.1093/brain/awq002 · Cited by 93
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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