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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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ResultClades of Adeno-Associated Viruses Are Widely Disseminated in Human Tissues
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Items 901–1,000 of 1,001
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Is RNA manipulation a viable therapy for spinal muscular atrophy?
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Yang, C., Hao, F., He, J., Lu, T., Klein, R. L., Zhao, L., & Duan, W. (2016) · Human Gene Therapy · doi:10.1089/hum.2015.083 · Cited by 12
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“In the case of AAV nanoparticles, it was discovered that certain AAV serotypes, e.g., AAV9, undergo transvascular transport across the BBB following an IV injection [7].”
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“…distinct targeting profiles: AAV1 and AAV6 efficiently transduce skeletal muscle, AAV5 targets airway epithelia and the CNS [97], AAV8 is hepatotropic [111], and AAV9 is notable for its ability to cross the vascular endothelium and transduce cardiomyocytes, skeletal muscle, and neurons [112,113].”
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Neuroanatomical Tract Tracers: Not Just for Neural Tracing Anymore
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Strategies and mechanisms of neuronal reprogramming
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Chemogenetic manipulation of astrocyte activity at the synapse— a gateway to manage brain disease
Pereira, M. J., Ayana, R., Holt, M. G., & Arckens, L. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1193130 · Cited by 10
“, 2017), scAAV9; chicken β-actin hybrid promoter (CB) promoter (Foust et al., 2009), and GfaABC1D promoter (Dashkoff et al.”
BackgroundJackson, K. L., Dayton, R. D., Fisher‐Perkins, J. M., Didier, P. J., Baker, K. C., Weimer, M. B., Gutierrez, A., Cain, C. D., Mathis, J. M., Gitcho, M. A., et al. (2015) · Journal of Medical Primatology · doi:10.1111/jmp.12162 · Cited by 9
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Current Advances in Vehicles for Brain Gene Delivery
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“[35] first demonstrated that after intravenous injection of AAV9 into neonatal animals, extensive transduction could be achieved including dorsal root ganglia, motor neurons throughout the spinal cord and neurons throughout the brain such as the neocortex, hippocam-”
BackgroundHistochemical localization of palmitoyl protein thioesterase-1 activity
Dearborn, J. T., Ramachandran, S., Shyng, C., Lu, J.-Y., Thornton, J., Hofmann, S. L., & Sands, M. S. (2015) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2015.11.004 · Cited by 10
“This at least partially explains the lack of efficacy in the treatment of murine INCL using intravenous enzyme replacement alone [15] and confirms that PPT1 does not readily cross theBBB.”
ResultInfluentialBrain endothelial cell‐targeted gene therapy of neurovascular disorders
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“Besides its efficacy at the diseased sites, two aspects of this liganddirected gene therapy are noteworthy in terms of clinical safety: (i) Overexpression of Nemo did not affect BBB tightness in 1 University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA.”
BackgroundInfluentialRecombinant AAV Delivery to the Central Nervous System
Bockstael, O., Foust, K. D., Kaspar, B. K., & Tenenbaum, L. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-370-7_7 · Cited by 10
Self-citationChimeric Capsid Proteins Impact Transduction Efficiency of Haploid Adeno-Associated Virus Vectors
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“AAV9 is superior for viral genome distribution such as to the brain, heart, liver, muscle, and other tissues via systemic administration [27,28].”
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“10 Administration of the rAAV9-MAG vector to Abcd1 - / - mice at P10 took advantage of the fact that the blood–brain barrier is still permeable to rAAV9 vector at this early age, 42 but rAAV9 can also transduce the CNS when administered IV to adult mice.”
Evolving therapies in neuronopathic LSDs: opportunities and challenges
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“Some specific AAV serotypes like the AAV9 and AAVrh10 have better CNS tropism and the ability to cross the blood brain barrier and reach the CNS via intravenous administration (Cearley and Wolfe 2006; Piguet, Alves, and Cartier 2017; Deverman et al. 2018; Foust et al. 2009).”
BackgroundGene therapy for Down syndrome
Fillat, C., & Altafaj, X. (2012) · Progress in brain research · doi:10.1016/b978-0-444-54299-1.00012-1 · Cited by 11
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Fiandaca, M. S., Bankiewicz, K. S., & Federoff, H. J. (2012) · Pharmaceuticals · doi:10.3390/ph5060553 · Cited by 10
“Differential targeting of the spinal cord in adult animals (especially humans) following iv administration of rAAV9 [120], offers a potential to bypass the BBB and delivering a genetic payload without invasive surgical procedures.”
BackgroundSlow Infusion of Recombinant Adeno-Associated Viruses into the Mouse Cerebrospinal Fluid Space
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“Furthermore, systemic AAV delivery can deliver body-wide gene expression in humans(14,15) and many animal models, with some vector serotypes able to cross the blood-brain barrier.(16,17)”
Tissue blood volumes and weights in adult beagle dogs.
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“Several AAVs, most notable AAV9 [81], overcome this by utilizing natural tropism for the central nervous system and the ability to bypass the BBB.”
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AAVs targeting human carbonic anhydrase IV enhance gene delivery to the brain
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“Moreover, its ability to transduce both neurons and glia makes it a versatile tool for developing combinatorial therapies addressing multiple epileptogenic pathways [13].”
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Kumar, J., Karim, A., Sweety, U. H., Sarma, H., Nurunnabi, M., & Narayan, M. (2023) · ACS Applied Bio Materials · doi:10.1021/acsabm.3c00842 · Cited by 9
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Neuronal Reprogramming for Brain Repair: Challenges and Perspectives
Bocchi, R., & Götz, M. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2020.08.006 · Cited by 9
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“…and been shown to exhibit unprecedented robust transduction in various tissues and organs by intravascular injection of the vector (Figure 1b) (Foust et al., 2009; Ghosh et al., 2007; Inagaki et al., 2006; Nakai et al., 2005a; Sarkar et al., 2006; Vandendriessche et al., 2007; Wang et al.,…”
Pourshafie, N., Lee, P. R., Chen, K., Harmison, G. G., Bott, L. C., Fischbeck, K. H., & Rinaldi, C. (2018) · Journal of Visualized Experiments · doi:10.3791/55724 · Cited by 9
“This approach has shown greater transduction efficacy in neonatal animals compared to adult animals, likely due to differences in extracellular matrix composition, neuron-to-glia ratio, and maturity of the blood-brain-barrier.(21,22)”
BackgroundAdvances in the treatment of neuronal ceroid lipofuscinosis
Sondhi, D., Rosenberg, J. B., de Graaf, B. G. V., Kaminsky, S. M., & Crystal, R. G. (2013) · Expert Opinion on Orphan Drugs · doi:10.1517/21678707.2013.852081 · Cited by 9
“There have been reports that specific serotype viral vectors such as AAV9 can cross the blood--brain barrier in mice [68-70] but require a large dose of virus (1.”
BackgroundChallenges for Gene Therapy of CNS Disorders and Implications for Parkinson's Disease Therapies
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“…by the Parkinson clinical gene therapy trials in mind, considerable scientific excitement surrounded the first reported AAV serotype able to cross the blood–brain barrier and efficiently transduce cells of the nervous system, AAV9 (Duque et al. , 2009; Foust et al. , 2009; Manfredsson et al. , 2009).”
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“There is a race for the development of AAV capsid variants affording good CNS transduction following systemic delivery and a new generation of BBB-penetrating AAV9 capsid variants has been made available ( Figure 5 ).”
Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice
Segur‐Bailach, E., Mateu-Bosch, A., Ros, X. B., Parés, M., da Silva‐Buttkus, P., Rathkolb, B., Gailus‐Durner, V., de Angelis, M. H., Moeini, P., González‐Aseguinolaza, G., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.07.022 · Cited by 8
“…fact that systemic AAV9 administration at advanced post-natal stages has limited transduction to the CNS, due to the reduced capacity of AAV9 to optimally cross the BBB. 23,38 In contrast, at neonatal stages, when BBB is not yet fully formed, transduction of the vector into the CNS can be achieved.”
Venkataraman, L., Jeanty, C. J., Kaniganti, T., Kennedy, B. J., Sullivan, P., Goldstein, D. S., & Kaler, S. G. (2025) · Science Advances · doi:10.1126/sciadv.adw5612 · Cited by 8
“The current study documents superior survival associated with enhanced efficiency of AAV9 transport into the mouse brain by intravenous delivery on P1, as noted by others ( 17 ).”
The brain-joint axis: links between osteoarthritis and neurodegenerative disorders in aging
Rabie, M. A., Madry, H., Cucchiarini, M., & Sayed, N. S. E. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.10.023 · Cited by 13
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Toward a gene therapy for neurological and somatic MPSIIIA
Haurigot, V., & Bosch, F. (2013) · Rare Diseases · doi:10.4161/rdis.27209 · Cited by 7
Subpial Adeno-associated Virus 9 (AAV9) Vector Delivery in Adult Mice
Tadokoro, T., Miyanohara, A., Navarro, M. R., Kamizato, K., Juhás, Š., Juhásová, J., Marsala, S., Platoshyn, O., Curtis, E., Gabel, B., et al. (2017) · Journal of Visualized Experiments · doi:10.3791/55770 · Cited by 8
Genetic dissection of the neuro-glio-vascular machinery in the adult brain
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“Tail vein injections were performed as previously described [18].”
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“In clinical trials, very high-dose of AAV9 vector (over 5×10(12) vg/ kg) has been proposed in patients with CNS or muscular disorders [13, 28].”
InfluentialCellular Reprogramming and Its Potential Application in Alzheimer’s Disease
Zhou, C., Ni, W., Zhu, T., Dong, S., Sun, P., & Hua, F. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.884667 · Cited by 8
“Their Frontiers in Neuroscience | www.frontiersin.org 3 April 2022 | Volume 16 | Article 884667 Zhou et al. Cellular Reprogramming in Alzheimer’s Disease main component is the aberrantly phosphorylated microtubuleassociated tau protein (Bennett et al., 2017; Fu et al., 2017).”
BackgroundSyndecan-4 Mediates the Cellular Entry of Adeno-Associated Virus 9
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“The pattern of gene delivery differs with age: neonatal subjects exhibit greater neuronal transduction than adults, which predominantly show astroglial versus neuronal transduction [36].”
BackgroundInfluentialThe Emerging Impact of microRNAs in Neurotrauma Pathophysiology and Therapy
Bhalala, O. G. (2015) · Europe PMC (PubMed Central) · Cited by 8
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“Consequently they are the alternative vehicle systems for modeling genetic disorders of the CNS, and have potential advantages over transgenic models [21–23].”
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Local transgene expression and whole‐body transgenesis to model brain diseases in nonhuman primate
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Therapeutics in paediatric genetic diseases: current and future landscape
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Gene therapy for disorders of the central nervous system
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“AAV9’s unique properties allow it to cross the blood–brain barrier (BBB) and target CNS tissues for gene delivery [37,38].”
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“Facial vein injection of AAV9-GFP into neonatal mice has resulted in extensive transduction of spinal cord and brain neurons [20].”
BackgroundMateu-Bosch, A., Segur‐Bailach, E., Muñoz‐Moreno, E., Barallobre, M. J., Arbonés, M. L., Gea‐Sorlí, S., Tort, F., Ribes, A., García‐Villoria, J., & Fillat, C. (2024) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2024.101276 · Cited by 7
Sangeetha, B., Leroy, K. I., & Kumar, B. (2024) · Cell Biochemistry and Function · doi:10.1002/cbf.70020 · Cited by 8
“The kinetics of gene expression were disclosed by the study, which helped to optimize the treatment plan for long ‐ lasting therapeutic benefits [118].”
Engineering brain-penetrant PROTACs: Bridging molecular design and CNS delivery
Li, X., Li, J., Sun, Y., Yao, T., Lu, Y., Liu, S., Li, H., Shi, Y., Chen, L., Zhao, Y., et al. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115876 · Cited by 8
VWA3A-derived ependyma promoter drives increased therapeutic protein secretion into the CSF
Carrell, E. M., Chen, Y. H., Ranum, P. T., Coffin, S. L., Singh, L. N., Tecedor, L., Keiser, M. S., Hudry, E., Hyman, B. T., & Davidson, B. L. (2023) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2023.07.016 · Cited by 8
Hayashi, Y., Sehara, Y., Watano, R., Ohba, K., Takayanagi, Y., Sakiyama, Y., Muramatsu, K., & Mizukami, H. (2024) · Human Gene Therapy · doi:10.1089/hum.2023.106 · Cited by 7
Strategies to target the central nervous system HIV reservoir
Mastrángelo, A., Gama, L., & Cinque, P. M. (2024) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0000000000000847 · Cited by 7
Systemic gene therapy corrects the neurological phenotype in a mouse model of NGLY1 deficiency
Du, A., Yang, K., Zhou, X., Ren, L., Liu, N., Zhou, C., Liang, J., Yan, N., Gao, G., & Wang, D. (2024) · JCI Insight · doi:10.1172/jci.insight.183189 · Cited by 7
“The groundbreaking discovery that a noninvasive systemic administration of rAAV9 can cross the BBB and achieve widespread CNS gene delivery (56, 57) has opened an exciting avenue to address neurological diseases, especially the conditions afflicting broad CNS compartments.”
BackgroundAdeno-Associated Viral Vectors in the Treatment of Epilepsy
Mullagulova, A. I., Евгеньевна, Т. Е., Solovyeva, V. V., Yakimov, A. M., Ibrahim, A., Дмитренко, Д. В., Sufianov, A. A., Суфианова, Г. З., & Rizvanov, A. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212081 · Cited by 10
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Molecular neurosurgery: vectors and vector delivery strategies
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“(Saito, 2006; Huang and Carcagno, 2018), or systemic injection of rAAV into the tail vein of adult or adolescent mice (Foust et al., 2009; Stoica et al., 2013; Körbelin et al., 2016; Thomsen et al., 2017) achieved similar expression of transfected or transduced genes in the mouse brain.”
BackgroundEngineering Cancer Selective Virotherapies: Are the Pieces of the Puzzle Falling into Place?
Swift, E. A., Pollard, S. M., & Parker, A. L. (2022) · Human Gene Therapy · doi:10.1089/hum.2022.178 · Cited by 7
“However, treating local tumors with oncolytic virotherapies may initiate immune priming and systemic abscopal effects.(11) Overcoming the systemic delivery challenge and identifying viral vectors that preferentially transduce tumor cells are therefore of the utmost importance; this will make trials easier and safer, a…”
BackgroundIgG-cleavage protein allows therapeutic AAV gene delivery in passively immunized MPS IIIA mice
Bobo, T. A., Samowitz, P. N., Robinson, M. I., Montes, L., Forsberg, L. J., Feng, R., Nicely, N. I., & Fu, H. (2022) · Gene Therapy · doi:10.1038/s41434-022-00368-9 · Cited by 7
“The demonstration of trans-blood-brain-barrier neurotropism of AAV9 [7, 8] has led to significant advancements in rAAV gene therapy for treating genetic diseases with global or broad neuropathies, supporting promising therapeutic potential [4–6, 9].”
BackgroundPEG-mediated transduction of rAAV as a platform for spatially confined and efficient gene delivery
Zou, L., Wang, J., Fāng, Y., & Tian, H. (2022) · Biomaterials Research · doi:10.1186/s40824-022-00322-1 · Cited by 7
“PEG‐enhanced rAAV expression in vitro We chose rAAV serotype 9 (rAAV9) to evaluate the effects of PEG additive on transgene expression because it has been widely used for gene delivery in the mammalian brain [37], especially well-suited for the transduction of neurons [38], and is currently being evaluated in clinical…”
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“25 In the present study, all organs examined, including the brain, showed increases in α -Gal A activity in the 1 (cid:1) 10 11 vg AAV9 group compared to mice treated with the same amount of AAV2.”
MethodSmith, M. C., Belur, L. R., Karlen, A. D., Erlanson, O., Furcich, J. W., Lund, T. C., Seelig, D. M., Kitto, K. F., Fairbanks, C. A., Kim, K. H., et al. (2024) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2024.101201 · Cited by 8
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Perinatal Gene Delivery to the CNS
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AAV Engineering Identifies a Species Barrier That Highlights a Portal to the Brain
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An Atoh1 CRE Knock-In Mouse Labels Motor Neurons Involved in Fine Motor Control
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AAV Gene Therapy Strategies for Lysosomal Storage Disorders with Central Nervous System Involvement
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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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