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Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates
Open accessAbstract
Injection of adeno-associated virus (AAV) into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals. In contrast to studies with other serotypes (AAV2, AAV4 and AAV5) in rodents, we report that a naturally occurring capsid (AAV9) and rationally engineered capsid (AAV2.5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP). Using either vector at a dose of ∼2 × 10(12) vector genome (vg) per 3-6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the central nervous system (CNS). AAV9 in particular displayed efficient transduction of spinal cord motor neurons. The peripheral organ biodistribution was highly reduced compared with intravascular delivery, and the presence of circulating anti-AAV-neutralizing antibodies up to a 1:128 titer had no inhibitory effect on CNS gene transfer. Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases.
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“The circulation of CSF delivers viral vectors to broader CNS regions when compared to IP injection [86].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [86]
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“in animal models, widespread coverage can be obtained by delivering the vector into the CSF”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [83]
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“Initial studies from Gray et al. (4) in cynomolgus macaques (nonhuman primates; NHPs) established that IT delivery of rAAV9 reaches all regions of the brain and spinal cord.”
Self-citationItson-Zoske, B., Shin, S. M., Hong, S., Yongsong, C., Fan, F., & Yu, H. (2026) · Molecular Therapy Advances · doi:10.1016/j.omta.2026.201794
“41 When targeting DRG innervation, IT injection reduces specificity due to AAV’s broad transduction and its potential to spread into the CNS, potentially causing off-target adverse effects.”
Chowdhury, E. A., Meno‐Tetang, G. M. L., Liu, S., Wu, S., Desireddy, N., Jerez, A., Mahmood, L., Rajwade, A., Bulusu, S., Jamier, T., et al. (2026) · Journal of Pharmacokinetics and Pharmacodynamics · doi:10.1007/s10928-026-10050-x
“While it has been well-established that both AAV5 and AAV9 vectors are effective for protein delivery to the CNS, the extent and location of AAV driven protein expression inside the brain seem to depend on the route of vector administration ( 2 , 4– 6 ).”
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Yu, Z., Li, Y., Zhang, Z., & Yin, R. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1901875
“In nonhuman primates, intrathecal AAV9 produced broad but incomplete CNS transduction (Gray et al., 2013).”
Mainardi, M., Brusco, S., Giannelli, S. G., Broccoli, V., & Colasante, G. (2026) · Epilepsia · doi:10.1002/epi.70517
Khalil, M., Bisignani, M., & Kandler, K. (2026) · Frontiers in Genome Editing · doi:10.3389/fgeed.2026.1946992
Metadata
- Authors
- Gray, S. J., Nagabhushan Kalburgi, S., McCown, T. J., & Jude Samulski, R.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Gene Therapy
- Published
- 2013-01-10
- Volume
- 20
- Issue
- 4
- Pages
- 450-459
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC3618620
- OpenAlex
- W2092757238
- Cited by
- 377
- References
- 30
- Citations by year
- 2026: 17 · 2025: 37 · 2024: 31 · 2023: 30 · 2022: 30 · 2021: 43 · 2020: 32 · 2019: 19 · 2018: 27 · 2017: 16 · 2016: 21 · 2015: 23 · 2014: 37 · 2013: 14
- FWCI
- 20.99
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-04-04)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (5u54ar056953-05)
- National Institute of Allergy and Infectious Diseases (R01AI072176)
- National Institute of Neurological Disorders and Stroke (NS 35633, R43NS063611, R01NS035633)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54-AR056953)
- National Center for Research Resources (UL1RR025747)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
- Keywords
- adeno-associated virus, AAV9, intrathecal gene delivery, cerebrospinal fluid injection, antibody escape, spinal cord, non-human primates, lysosomal storage disease, motor neuron disease, vector biodistribution
- MeSH terms
- Dependovirus, Animals, Blood Vessels, Brain, Genetic Vectors, Injections, Spinal, Macaca fascicularis, Mice, Inbred BALB C, Motor Neurons, Spinal Cord, Tissue Distribution, Transduction, Genetic, Rats, Sprague-Dawley, Mice, Rats, Antibodies, Neutralizing
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