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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Albright, BH; Storey, CM; Murlidharan, G; Castellanos Rivera, RM; Berry, GE; Madigan, VJ; Asokan, A

Published Date

  • February 7, 2018

Published In

Volume / Issue

  • 26 / 2

Start / End Page

  • 510 - 523

PubMed ID

  • 29175157

Pubmed Central ID

  • PMC5835146

Electronic International Standard Serial Number (EISSN)

  • 1525-0024

Digital Object Identifier (DOI)

  • 10.1016/j.ymthe.2017.10.017


  • eng

Conference Location

  • United States