Variants of the adeno-associated virus serotype 9 with enhanced penetration of the blood–brain barrier in rodents and primates
Abstract
The development of gene therapies for the treatment of diseases of the central nervous system has been hindered by the limited availability of adeno-associated viruses (AAVs) that efficiently traverse the blood-brain barrier (BBB). Here, we report the rational design of AAV9 variants displaying cell-penetrating peptides on the viral capsid and the identification of two variants, AAV.CPP.16 and AAV.CPP.21, with improved transduction efficiencies of cells of the central nervous system on systemic delivery (6- to 249-fold across 4 mouse strains and 5-fold in cynomolgus macaques, with respect to the AAV9 parent vector). We also show that the neurotropism of AAV.CPP.16 is retained in young and adult macaques, that this variant displays enhanced transcytosis at the BBB as well as increased efficiency of cellular transduction relative to AAV9, and that it can be used to deliver antitumour payloads in a mouse model of glioblastoma. AAV capsids that can efficiently penetrate the BBB will facilitate the clinical translation of gene therapies aimed at the central nervous system.
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Bioengineering of novel AAV variants for BBB-crossing and CNS targeting has achieved some successes, yielding AAV.CPP.16, AAV.CAP-B10, and AAV.cc47 with variable enhancements over AAV9 from mice to NHPs.
“The bioengineering of novel AAV variants in terms of BBB-crossing and CNS targeting has achieved some successes in recent years, yielding AAV.CPP.16 [57], AAV.CAP-B10 [68] and AAV.cc47 [111] with variable enhancements over AAV9 from mice to NHPs.”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [57]
The superiority of AAV.CPP.16 over AAV9 can translate from mice to non-human primates, showing 6- to 249-fold enhancement across 4 mouse strains and fivefold enhancement in non-human primates in CNS transduction after intravenous delivery.
“Strikingly, the superiority of AAV.CPP.16 over AAV9 can translate from mice to non-human primates, showing 6- to 249-fold enhancement across 4 mouse strains and fivefold enhancement in non-human primates (NHPs) in CNS transduction after intravenous delivery [57].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [57]
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References 74 · Cited by 120
- Authors
- Yao, Y., Wang, J., Liu, Y., Qu, Y., Wang, K., Zhang, Y., Chang, Y., Yang, Z., Wan, J., Liu, J., Nakashima, H., Lawler, S. E., Chiocca, E. A., Cho, C.-F., & Bei, F.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Bei, Fengfeng
- ORCID
- Venue
- Nature Biomedical Engineering
- Published
- 2022-10-10
- Volume
- 6
- Issue
- 11
- Pages
- 1257-1271
- ISSN
- 2157-846X (ISSN-L)
- OpenAlex
- W4304080890
- Cited by
- 120
- References
- 74
- Citations by year
- 2026: 22 · 2025: 36 · 2024: 38 · 2023: 21 · 2022: 2
- FWCI
- 14.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Biomedical Engineering (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brigham and Women's Hospital
- 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, cell-penetrating peptides, blood-brain barrier penetration, central nervous system gene therapy, transcytosis, neurotropism, systemic drug delivery, glioblastoma, cynomolgus macaques, mouse model
- MeSH terms
- Dependovirus, Animals, Blood-Brain Barrier, Genetic Vectors, Macaca, Primates, Rodentia, Transduction, Genetic, Mice, Serogroup
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