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

Publication ,  Journal Article
Albright, BH; Storey, CM; Murlidharan, G; Castellanos Rivera, RM; Berry, GE; Madigan, VJ; Asokan, A
Published in: Mol Ther
February 7, 2018

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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Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

February 7, 2018

Volume

26

Issue

2

Start / End Page

510 / 523

Location

United States

Related Subject Headings

  • Transgenes
  • Transduction, Genetic
  • Tissue Distribution
  • Protein Binding
  • Phylogeny
  • Organ Specificity
  • Myocardium
  • Models, Molecular
  • Mice
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
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Albright, B. H., Storey, C. M., Murlidharan, G., Castellanos Rivera, R. M., Berry, G. E., Madigan, V. J., & Asokan, A. (2018). Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier. Mol Ther, 26(2), 510–523. https://doi.org/10.1016/j.ymthe.2017.10.017
Albright, Blake H., Claire M. Storey, Giridhar Murlidharan, Ruth M. Castellanos Rivera, Garrett E. Berry, Victoria J. Madigan, and Aravind Asokan. “Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier.Mol Ther 26, no. 2 (February 7, 2018): 510–23. https://doi.org/10.1016/j.ymthe.2017.10.017.
Albright BH, Storey CM, Murlidharan G, Castellanos Rivera RM, Berry GE, Madigan VJ, et al. Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier. Mol Ther. 2018 Feb 7;26(2):510–23.
Albright, Blake H., et al. “Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier.Mol Ther, vol. 26, no. 2, Feb. 2018, pp. 510–23. Pubmed, doi:10.1016/j.ymthe.2017.10.017.
Albright BH, Storey CM, Murlidharan G, Castellanos Rivera RM, Berry GE, Madigan VJ, Asokan A. Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier. Mol Ther. 2018 Feb 7;26(2):510–523.

Published In

Mol Ther

DOI

EISSN

1525-0024

Publication Date

February 7, 2018

Volume

26

Issue

2

Start / End Page

510 / 523

Location

United States

Related Subject Headings

  • Transgenes
  • Transduction, Genetic
  • Tissue Distribution
  • Protein Binding
  • Phylogeny
  • Organ Specificity
  • Myocardium
  • Models, Molecular
  • Mice
  • Humans