Global CNS Transduction of Adult Mice by Intravenously Delivered rAAVrh.8 and rAAVrh.10 and Nonhuman Primates by rAAVrh.10
Open accessAbstract
Some recombinant adeno-associated viruses (rAAVs) can cross the neonatal blood-brain barrier (BBB) and efficiently transduce cells of the central nervous system (CNS). However, in the adult CNS, transduction levels by systemically delivered rAAVs are significantly reduced, limiting their potential for CNS gene therapy. Here, we characterized 12 different rAAVEGFPs in the adult mouse CNS following intravenous delivery. We show that the capability of crossing the adult BBB and achieving widespread CNS transduction is a common character of AAV serotypes tested. Of note, rAAVrh.8 is the leading vector for robust global transduction of glial and neuronal cell types in regions of clinical importance such as cortex, caudate-putamen, hippocampus, corpus callosum, and substantia nigra. It also displays reduced peripheral tissue tropism compared to other leading vectors. Additionally, we evaluated rAAVrh.10 with and without microRNA (miRNA)-regulated expressional detargeting from peripheral tissues for systemic gene delivery to the CNS in marmosets. Our results indicate that rAAVrh.8, along with rh.10 and 9, hold the best promise for developing novel therapeutic strategies to treat neurological diseases in the adult patient population. Additionally, systemically delivered rAAVrh.10 can transduce the CNS efficiently, and its transgene expression can be limited in the periphery by endogenous miRNAs in adult marmosets.
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AAVrh.8 and AAVrh.10 naturally isolated from rhesus macaques have enhanced CNS tropism in adult mice following IV injection.
“Besides AAV9, naturally isolated AAVrh.8 and AAVrh.10 from rhesus macaques were validated with enhanced CNS tropism in adult mice following IV injection [125].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [125]
The Introduction reports testing rAAVrh.8 and rAAVrh.10 in adult mice after systemic delivery, and the Discussion says both were among the vectors with the strongest CNS transduction after IV injection. Our copy does not state that these vectors were naturally isolated from rhesus macaques, so it does not support that origin detail. (LLM, conf=0.82)
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Self-citation
- Authors
- Yang, B., Li, S., Wang, H., Guo, Y., Gessler, D. J., Cao, C., Su, Q., Kramer, J., Zhong, L., Ahmed, S. S., Zhang, H., He, R., Desrosiers, R. C., Brown, R., Xu, Z., & Gao, G.
- Affiliations
- California Institute of Technology (US)
- University of Massachusetts Chan Medical School (US)
- Hebei Medical University (CN)
- Tongji University (CN)
- Harvard University (US)
- Corresponding author
- Xu, Zuoshang
- Gao, Guangping
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 22
- Issue
- 7
- Pages
- 1299-1309
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC4089005
- OpenAlex
- W2092420017
- Semantic Scholar
- 20ad2dfc2f41705f9cc02ed45eaaacb3f4ac9fc1
- Cited by
- 213
- References
- 49
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 21 · 2023: 10 · 2022: 14 · 2021: 28 · 2020: 14 · 2019: 17 · 2018: 14 · 2017: 16 · 2016: 26 · 2015: 26 · 2014: 13
- FWCI
- 16.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- Foundation for the National Institutes of Health
- Johns Hopkins University
- Voyager Therapeutics
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS059708, R01NS076991)
- National Center for Research Resources
- 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
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- recombinant adeno-associated virus vectors, intravenous gene delivery, CNS gene therapy, marmoset, AAV serotypes
- MeSH terms
- Dependovirus, Animals, Brain, Callithrix, Central Nervous System, Male, Primates, MicroRNAs, Mice
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