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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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Cites
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Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy
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BackgroundStructure of neurotropic adeno-associated virus AAVrh.8
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“D) from ideal bond lengths and angles were obtained from the CNS program (Brunger et al., 1998) and the average Bfactor for the VP3 model, solvent molecules, NT, and ions were calculated using the MOLEMAN program (Kleywegt and Jones, 1997).”
BackgroundInfluentialPyruvate dehydrogenase complex deficiency and its relationship with epilepsy frequency – An overview
Bhandary, S., & Aguan, K. (2015) · Epilepsy Research · doi:10.1016/j.eplepsyres.2015.07.002 · Cited by 65
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Locating and labeling neural stem cells in the brain
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“AAV9 can infect adult astrocytes when administered intravenously which is a much less invasive than stereotaxic administration that in itself also is a form of injury that might affect stem cell behavior (Foust et al., 2009).”
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TRIM11 Prevents and Reverses Protein Aggregation and Rescues a Mouse Model of Parkinson’s Disease
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“Gene transfer mediated by AAVs has become an important approach for treating CNS disorders (Deverman et al., 2018), and its potential is emphasized by recent positive outcomes in clinical trials (Mendell et al., 2017).”
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ResultThe role of the efflux transporter, P‐glycoprotein, at the blood–brain barrier in drug discovery
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“However, the adeno‐associated virus 9, when administered via intravenous injection, is able to bypass the BBB and exert an effect (Foust et al., 2009).”
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“intravenous injections has been reported in another study using AAV2/9-GFP vectors (Foust et al., 2009).”
InfluentialAdenoviral vectors for in vivo delivery of CRISPR-Cas gene editors
Rice-Boucher, P. J., Cui, X., & Curiel, D. T. (2020) · Journal of Controlled Release · doi:10.1016/j.jconrel.2020.09.003 · Cited by 62
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“Onasemnogene consists of a blood-brain-barrier penetrant adeno associated virus serotype 9 (AAV9) expressing SMN1 cDNA under a chicken beta actin hybrid promoter [26].”
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“118,119 To address this, researchers have developed advanced AAV variants with improved tropism and BBB penetration through rational design and screening of the AAV capsid.”
BackgroundAdeno-Associated Virus Vectors: Principles, Practices, and Prospects in Gene Therapy
Zwi‐Dantsis, L., Mohamed, S., Massaro, G., & Moeendarbary, E. (2025) · Viruses · doi:10.3390/v17020239 · Cited by 68
“AAV9 is currently the preferred vector for broad CNS transduction, although studies have also utilized capsids such as AAV2, AAV6, AAV9, AAVrh10, and AAVhu [123,124].”
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“Some serotypes, such as AAV9 family of vectors, can cross the BBB and transduce endothelial cells, neurons and astrocytes throughout the CNS and PNS, as well as somatic tissues after a single administration into either the blood or the CSF [76, 80–85].”
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“Recently, Foust et al. (2009) reported that a single intravenous injection of scAAV serotype-9 vector into newborn mice provided gene transfer across the BBB into the CNS.”
BackgroundMarshall, M. S., Issa, Y., Jakubauskas, B., Stoskute, M., Elackattu, V., Marshall, J. N., Bogue, W., Nguyen, D. A., Hauck, Z., Rue, E. A., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.01.009 · Cited by 60
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BackgroundInfluentialExtensive Transduction and Enhanced Spread of a Modified AAV2 Capsid in the Non-human Primate CNS
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“In particular, intravenous injection of recombinant AAV9 led to robust motoneuron transduction in newborn mice (Duque et al. , 2009; Foust et al. , 2009; Miyake et al. , 2011; Zhang et al. , 2011).”
InfluentialLópez-Gordo, E., Chamberlain, K., Riyad, J. M., Kohlbrenner, E., & Weber, T. (2024) · Viruses · doi:10.3390/v16030442 · Cited by 68
Arnold, E. S., & Fischbeck, K. H. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-64076-5.00038-7 · Cited by 58
Merienne, N., Douce, J. L., Faivre, E., Déglon, N., & Bonvento, G. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00106 · Cited by 58
“Indeed, the development of highly efficient viral vectors for gene transfer in the CNS is providing new systems for localized and controlled gene expression.”
BackgroundInfluentialNizzardo, M., Simone, C., Rizzo, F., Salani, S., Dametti, S., Rinchetti, P., Bo, R. D., Foust, K. D., Kaspar, B. K., Bresolin, N., et al. (2015) · Science Advances · doi:10.1126/sciadv.1500078 · Cited by 58
Self-citationAAV9-mediated central nervous system–targeted gene delivery via cisterna magna route in mice
Lukashchuk, V., Lewis, K. E. A., Coldicott, I., Grierson, A. J., & Azzouz, M. (2016) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2015.55 · Cited by 60
Vagner, T., Dvorzhak, A., Wójtowicz, A. M., Harms, C., & Grantyn, R. (2016) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2016.10.007 · Cited by 59
Amado, D. A., Rieders, J., Diatta, F. H., Hernandez‐Con, P., Singer, A., Mak, J. T., Zhang, J., Lancaster, E., Davidson, B. L., & Chen‐Plotkin, A. S. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.11.013 · Cited by 58
“Elicits an Inflammatory Response and Ependymal Hypertrophy AAV9 transduces multiple cell types, including neurons and glia.(48) Therefore, we asked whether the observed inflammatory response and subsequent hippocampal degeneration were serotype specific.”
BackgroundWatanabe, S., Kanatsu‐Shinohara, M., Ogonuki, N., Matoba, S., Ogura, A., & Shinohara, T. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.005 · Cited by 58
“Moreover, the molecular composition is also different: the BBB is composed of CLDN1, CLDN3, CLDN5, and CLDN12 (Schrade et al., 2012), but a different set of claudins, including CLDN3, CLDN5, and CLDN11, contribute to the BTB (Gow et al., 1999; Meng et al., 2005; Morrow et al., 2009).”
InfluentialDifferences in MPS I and MPS II Disease Manifestations
Hampe, C. S., Yund, B. D., Orchard, P. J., Lund, T. C., Wesley, J. B., & McIvor, R. S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22157888 · Cited by 59
Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective
Donfrancesco, A. D., Massaro, G., Meo, I. D., Tiranti, V., Bottani, E., & Brunetti, D. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14061287 · Cited by 62
“10), have shown u ique properties to target the CNS in com arison to most AAV serotypes [73], making th m a powerful system for delivering genetic material to CNS sin e they both shar the ability to cross the blood– brain barrier (BBB) [74].”
BackgroundRetinal Ganglion Cell Gene Therapy and Visual System Repair
Hellström, M., & Harvey, A. R. (2011) · Current Gene Therapy · doi:10.2174/156652311794940746 · Cited by 57
“The rAAV2/9 vector can also cross the blood brain barrier and transduce neurons (and adult astrocytes) in the young and adult brain and spinal cord following injection to the bloodstream [163, 164], including neonatal retinal ganglion cells [165].”
BackgroundGene therapy for Huntington's disease
Ramaswamy, S., & Kordower, J. H. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.12.030 · Cited by 61
“by penetrating the gap junctions and being taken up by astrocytic end feet (Foust et al., 2009).”
BackgroundAxonal transport of AAV9 in nonhuman primate brain
Green, F., Samaranch, L., Zhang, H. S., Manning-Bog, A., Meyer, K., Forsayeth, J., & Bankiewicz, K. S. (2016) · Gene Therapy · doi:10.1038/gt.2016.24 · Cited by 57
Huda, F., Konno, A., Matsuzaki, Y., Goenawan, H., Miyake, K., Shimada, T., & Hirai, H. (2014) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2014.32 · Cited by 58
Development of an AAV-Based MicroRNA Gene Therapy to Treat Machado-Joseph Disease
Martier, R., Sogorb-González, M., Stricker-Shaver, J., Hübener‐Schmid, J., Keskin, S., Klı́ma, J., Toonen, L. J. A., Juhás, Š., Juhásová, J., Ellederová, Z., et al. (2019) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2019.10.008 · Cited by 57
“semiovaleWM, (53) temporal cortex, (54) temporal lobeWM, (55) insular cortex, (56) caudate, (57) thalamus anterior, (58) thalamus ventral, (59) putamen, (60) globus pallidus,”
Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease
Cain, J. T., Likhite, S., White, K. A., Timm, D. J., Davis, S. S., Johnson, T. B., Dennys-Rivers, C. N., Rinaldi, F., Motti, D., Corcoran, S., et al. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.06.015 · Cited by 53
“CLN6 was produced by transient transfection procedures using a double-stranded AAV2-inverted terminal repeat (ITR)-based CB-CLN6 vector, with a plasmid encoding the Rep2Cap9 sequence, as previously described, along with an adenoviral helper plasmid pHelper (Stratagene, Santa Clara, CA) in HEK293 cells.(34) The purity…”
MethodSelf-citationMarrone, L., Marchi, P. M., & Azzouz, M. (2022) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2012148 · Cited by 56
Ye, D., Chukwu, C., Yang, Y., Hu, Z., & Chen, H. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115363 · Cited by 60
Zheng, H., Qiao, C., Wang, C., Li, J., Li, J., Yuan, Z., Zhang, C., & Xiao, X. (2009) · Human Gene Therapy · doi:10.1089/hum.2009.131 · Cited by 56
“We have two important observations that further support the notion of retrograde transport from nerve endings in the muscle to the neuron cell bodies, rather than systemically crossing the BBB by AAV8.”
InfluentialDashkoff, J., Lerner, P., Truong, N., Klickstein, J. A., Fan, Z., Mu, D., Maguire, C. A., Hyman, B. T., & Hudry, E. (2016) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2016.81 · Cited by 57
Rincón, M. Y., de Vin, F., Duqué, S. I., Fripont, S., Castaldo, S. A., Wenger, J. B., & Holt, M. G. (2018) · Gene Therapy · doi:10.1038/s41434-018-0005-z · Cited by 57
Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier
Bowser, L. E., Young, M., Wenger, O. K., Ammous, Z., Brigatti, K. W., Carson, V. J., Moser, T., Deline, J., Aoki, K., Morlet, T. G., et al. (2019) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2019.01.013 · Cited by 57
Highly Efficient Ultracentrifugation-free Chromatographic Purification of Recombinant AAV Serotype 9
Tomono, T., Hirai, Y., Okada, H., Miyagawa, Y., Adachi, K., Sakamoto, S., Kawano, Y., Chono, H., Mineno, J., Ishii, A., et al. (2018) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2018.10.015 · Cited by 55
Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery
Joshi, C. R., Labhasetwar, V., & Ghorpade, A. (2017) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-016-9724-3 · Cited by 55
“…antibodies to AAV and EPO (Yang et al. 2013) Crosses blood-brain barrier, neonatal mice: neuronal tropism, adult mice: astrocyte tropism (Foust et al. 2009) GFP Spinal muscular atrophy (SMA) Motor neurons, Astrocytes Survival motor neurons Δ7 and B6 mice Intramuscular injection…”
InfluentialBesse, A., Astord, S., Marais, T., Roda, M., Giroux, B., Lejeune, F., Relaix, F., Smeriglio, P., Barkats, M., & Biferi, M. G. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.05.011 · Cited by 53
The progress of AAV-mediated gene therapy in neuromuscular disorders
Aguti, S., Malerba, A., & Zhou, H. (2018) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2018.1479739 · Cited by 62
“AAV9 is able to cross the blood–brain barrier (BBB), allowing intravenous administration rather than intrathecal injection into the spinal cord, as is currently used in Spinraza AON drug treatment [60,61].”
MethodAdeno-Associated Virus (AAV) Gene Delivery: Dissecting Molecular Interactions upon Cell Entry
Large, E. E., Silveria, M., Zane, G. M., Weerakoon, O., & Chapman, M. S. (2021) · Viruses · doi:10.3390/v13071336 · Cited by 57
“AAV9 had early promise as a treatment for CNS disorders because strong CNS expression was observed in small and large mammalian models [136–138] and AAV9 can pass through the mouse BBB but to a limited extent [136].”
BackgroundMatagne, V., Borloz, E., Ehinger, Y., Saidi, L., Villard, L., & Roux, J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105235 · Cited by 54
“…was made in the field of CNS gene therapy (Hocquemiller et al., 2016), in part due to the use of the adeno-associated virus 9 (AAV9) that is capable of crossing the blood brain barrier and transduce brain cells after intravenous injection (Duque et al., 2009; Foust et al., 2009; Gray et al., 2011).”
MethodChatterjee, D., Marmion, D. J., McBride, J. L., Manfredsson, F. P., Butler, D., Messer, A. C., & Kordower, J. H. (2021) · Gene Therapy · doi:10.1038/s41434-021-00244-y · Cited by 55
Pénzes, J. J., Chipman, P. R., Bhattacharya, N., Zeher, A., Huang, R. K., McKENNA, R. V., & Agbandje‐McKenna, M. (2021) · Journal of Virology · doi:10.1128/jvi.00843-21 · Cited by 55
“Previously, VRI was reported to be associated with the blood-brain barrier (BBB) crossing ability of both AAV9 and AAVrh10 (26, 68).”
BackgroundInfluentialTukov, F. F., Mansfield, K. G., Milton, M., Meseck, E. K., Penraat, K. A., Chand, D. H., & Hartmann, A. (2022) · Human Gene Therapy · doi:10.1089/hum.2021.255 · Cited by 54
Efficacy of gene delivery to the brain using AAV and ultrasound depends on serotypes and brain areas
Kofoed, R. H., Dibia, C. L., Noseworthy, K., Xhima, K., Vacaresse, N., Hynynen, K., & Aubert, I. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.09.048 · Cited by 59
Efficient CNS gene delivery by intravenous injection
Louboutin, J., Chekmasova, A. A., Marusich, E., Chowdhury, J. R., & Strayer, D. S. (2010) · Nature Methods · doi:10.1038/nmeth.1518 · Cited by 54
Intravenous AAV9 efficiently transduces myenteric neurons in neonate and juvenile mice
Gombash, S. E., Cowley, C. J., Fitzgerald, J. A., Hall, J. C. E., Mueller, C., Christofi, F. L., & Foust, K. D. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00081 · Cited by 55
“The paucity of enteric glia transduction was surprising because we previously reported that scAAV-CB-GFP expression was highly efficient in CNS astrocytes (Foust et al., 2009).”
BackgroundMethodInfluentialSelf-citationGene-based therapies for dominantly inherited retinopathies
Farrar, G. J., Millington‐Ward, S., Chadderton, N., Humphries, P., & Kenna, P. F. (2011) · Gene Therapy · doi:10.1038/gt.2011.172 · Cited by 54
Pépin, D., Sosulski, A., Zhang, L., Wang, D., Vathipadiekal, V., Hendren, K., Coletti, C. M., Yu, A., Castro, C. M., Birrer, M. J., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510604112 · Cited by 54
“The AAV9 serotype of the AAV family has been safely used to infect a range of cells and tissues, including cardiac myocytes (37), lung tissue (38), and neurons of the CNS and peripheral nervous system (17, 39–43), to correct a host of genetic diseases, including ALS (39, 40, 43), Parkinson’s (44), Huntington’s (45–51)…”
BackgroundWu, Y. F., Mao, W. F., Zhou, Y. L., Wang, X. T., Liu, P. Y., & Tang, J. B. (2015) · Gene Therapy · doi:10.1038/gt.2015.97 · Cited by 54
Tropak, M. B., Yonekawa, S., Karumuthil‐Melethil, S., Thompson, P., Wakarchuk, W. W., Gray, S. J., Walia, J. S., Mark, B. L., & Mahuran, D. J. (2016) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2015.57 · Cited by 54
Boisgérault, F., & Mingozzi, F. (2015) · Current Gene Therapy · doi:10.2174/1566523215666150630121750 · Cited by 54
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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