Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders
Open accessAbstract
Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood-brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations.
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After intrathecal delivery, vectors stay predominantly in the lower spine.
“The vectors stay predominantly in the lower spine in intrathecal delivery administrations.”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [92]
The Results section on AAV9 injection into the cerebrospinal fluid reports extensive motor-neuron transduction at all levels of the spinal cord after intrathecal injection at L5, not confinement to the lower spine. The Materials and Methods section also reports confirmed rostral and caudal intrathecal flow. Page numbers are not available in our copy. (LLM, conf=0.85)
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Experimental — accuracy not yet measuredUse of intrathecal delivery for gene therapy vectors has been limited to studies involving spinal cord and peripheral nerve disease.
“Use of intrathecal delivery for gene therapy vectors has been limited to studies involving spinal cord and peripheral nerve disease.”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [92]
The Results section, “AAV9 injection into the CSF produces transgene expression in the brain” (page unavailable), reports examining brain expression after intrathecal or cisternal vector injection in piglets. The paper therefore does not confine its investigation of intrathecal gene delivery to spinal cord and peripheral nerve disease, as the claim says. (LLM, conf=0.81)
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- Authors
- Bevan, A. K., Duque, S., Foust, K. D., Morales, P. R., Braun, L., Schmelzer, L., Chan, C. M., McCrate, M., Chicoine, L. G., Coley, B. D., Porensky, P. N., Kolb, S. J., Mendell, J. R., Burghes, A. H., & Kaspar, B. K.
- Affiliations
- Nationwide Children's Hospital (US)
- The Ohio State University (US)
- Corresponding author
- Kaspar, Brian K
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 19
- Issue
- 11
- Pages
- 1971-1980
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC3222525
- OpenAlex
- W1967242914
- Cited by
- 337
- References
- 50
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 19 · 2023: 14 · 2022: 22 · 2021: 31 · 2020: 23 · 2019: 23 · 2018: 28 · 2017: 22 · 2016: 26 · 2015: 31 · 2014: 28 · 2013: 27 · 2012: 21
- FWCI
- 15.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R21NS064328, RC2NS069476, K08NS067282, RC2 NS69476-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- AAV9, adeno-associated virus vectors, systemic gene delivery, blood-brain barrier penetration, spinal muscular atrophy, lysosomal storage disease, cerebrospinal fluid injection, motor neurons, dorsal root ganglion neurons, glial cells, cynomolgus macaques, large animal model
- MeSH terms
- Dependovirus, Animals, Brain, Gene Expression Regulation, Genetic Vectors, Humans, Injections, Epidural, Injections, Intra-Arterial, Macaca, Male, Motor Neurons, Muscular Atrophy, Spinal, Neuroglia, Spinal Cord, Swine, Time Factors, Transduction, Genetic, Genetic Therapy, Gene Transfer Techniques, Muscle, Skeletal, Transgenes, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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