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Cited by 82Virus-based gene therapy researchBarrier Structure and Function StudiesRNA Interference and Gene Delivery

Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier

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Albright, Blake H., Storey, Claire M., Murlidharan, Giridhar, Castellanos Rivera, Ruth M., Berry, Garrett E., Madigan, Victoria J., Asokan, Aravind·2018·Molecular Therapy
DOI 10.1016/j.ymthe.2017.10.017PMC PMC5835146
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Abstract

Effective gene delivery to the CNS by intravenously administered adeno-associated virus (AAV) vectors requires crossing the blood-brain barrier (BBB). To achieve therapeutic CNS transgene expression, high systemic vector doses are often required, which poses challenges such as scale-up costs and dose-dependent hepatotoxicity. To improve the specificity and efficiency of CNS gene transfer, a better understanding of the structural features that enable AAV transit across the BBB is needed. We generated a combinatorial domain swap library using AAV1, a serotype that does not traverse the vasculature, and AAVrh.10, which crosses the BBB in mice. We then screened individual variants by phylogenetic and structural analyses and subsequently conducted systemic characterization in mice. Using this approach, we identified key clusters of residues on the AAVrh.10 capsid that enabled transport across the brain vasculature and widespread neuronal transduction in mice. Through rational design, we mapped a minimal footprint from AAVrh.10, which, when grafted onto AAV1, confers the aforementioned CNS phenotype while diminishing vascular and hepatic transduction through an unknown mechanism. Functional mapping of this capsid surface footprint provides a roadmap for engineering synthetic AAV capsids for efficient CNS gene transfer with an improved safety profile.

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  • Albright and colleagues identified essential 8 amino acid residues on the AAVrh.10 capsid that mediated transport across the BBB and grafted them onto AAV1 capsid, enabling the new chimeric capsid to cross the BBB and preferentially transduce neurons in C57/Bl6 mice.

    “Moreover, Albright and colleagues identified the essential 8 amino acid residues on the AAVrh.10 capsid that mediated transport across the BBB and grafted onto AAV1 capsid, enabling the new chimeric capsid to cross the BBB and preferentially transduced neurons in C57/Bl6 mice [58].”

    From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [58]

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  1. [1]1. [Berns, K., and Parrish, C. (2007). Parvoviridae. In Fields Virology, D.M. Knipe, P.M. Howley, D.E. Grif fi n, R.A. Lamb, M.A. Martin, B. Roizman, and S.E. Straus, eds. (Lippincott Williams & Wilkins), pp. 2437 -2477.](http://refhub.elsevier.com/S1525-0016(17)30533-6/sref1)
  2. [27]27. [Wu, Z., Miller, E., Agbandje-McKenna, M., and Samulski, R.J. (2006). Alpha2,3 and alpha2,6 N-linked sialic acids facilitate ef fi cient binding and transduction by adenoassociated virus types 1 and 6. J. Virol. 80 , 9093 -9103.](http://refhub.elsevier.com/S1525-0016(17)30533-6/sref27)
  3. [30]30. [Rosenberg, J.B., Sondhi, D., Rubin, D.G., Monette, S., Chen, A., Cram, S., De, B.P., Kaminsky, S.M., Sevin, C., Aubourg, P., and Crystal, R.G. (2014). Comparative ef fi cacy and safety of multiple routes of direct CNS administration of adeno-associated virus gene transfer vector serotype rh.10 expressing the human arylsulfatase A cDNA to nonhuman primates. Hum. Gene Ther. Clin. Dev. 25 , 164 -177.](http://refhub.elsevier.com/S1525-0016(17)30533-6/sref30)
  4. [36]36. [Nathwani, A.C., Reiss, U.M., Tuddenham, E.G.D., Rosales, C., Chowdary, P., McIntosh, J., Della Peruta, M., Lheriteau, E., Patel, N., Raj, D., et al. (2014). Longterm safety and ef fi cacy of factor IX gene therapy in hemophilia B. N. Engl. J. Med. 371 , 1994 -2004.](http://refhub.elsevier.com/S1525-0016(17)30533-6/sref36)

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Authors
Albright, B. H., Storey, C. M., Murlidharan, G., Castellanos Rivera, R. M., Berry, G. E., Madigan, V. J., & Asokan, A.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Asokan, Aravind
ORCID
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2018-02
Volume
26
Issue
2
Pages
510-523
ISSN
1525-0016 (ISSN-L)
DOI
10.1016/j.ymthe.2017.10.017
PMC
PMC5835146
OpenAlex
W2767047931
Cited by
82
References
49
Citations by year
2026: 6 · 2025: 8 · 2024: 7 · 2023: 5 · 2022: 13 · 2021: 16 · 2020: 8 · 2019: 8 · 2018: 11
FWCI
4.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • NIH (R01HL089221, P01HL112761)
  • UNC (T32AI007419)
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
AAV1, blood-brain barrier penetration, neuronal transduction, AAV capsid engineering, hepatotoxicity, systemic gene therapy
MeSH terms
Dependovirus, Animals, Biological Transport, Blood-Brain Barrier, Brain, Genetic Engineering, Genetic Vectors, Humans, Models, Molecular, Myocardium, Organ Specificity, Phylogeny, Protein Binding, Tissue Distribution, Transduction, Genetic, Gene Expression, Gene Transfer Techniques, Transgenes, Capsid Proteins, Mice

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