Structural characterization of a novel human adeno-associated virus capsid with neurotropic properties

Hung-Lun Hsu, Alexander Brown, Anna B. Loveland, Anoushka Lotun, Meiyu Xu, Li Luo, Guangchao Xu, Jia Li, Lingzhi Ren, Qin Su, Dominic J. Gessler, Yuquan Wei, Phillip W. L. Tai (), Andrei A. Korostelev () and Guangping Gao ()
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Hung-Lun Hsu: University of Massachusetts Medical School
Alexander Brown: University of Massachusetts Medical School
Anna B. Loveland: University of Massachusetts Medical School
Anoushka Lotun: University of Massachusetts Medical School
Meiyu Xu: University of Massachusetts Medical School
Li Luo: University of Massachusetts Medical School
Guangchao Xu: University of Massachusetts Medical School
Jia Li: University of Massachusetts Medical School
Lingzhi Ren: University of Massachusetts Medical School
Qin Su: University of Massachusetts Medical School
Dominic J. Gessler: University of Massachusetts Medical School
Yuquan Wei: Sichuan University
Phillip W. L. Tai: University of Massachusetts Medical School
Andrei A. Korostelev: University of Massachusetts Medical School
Guangping Gao: University of Massachusetts Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Recombinant adeno-associated viruses (rAAVs) are currently considered the safest and most reliable gene delivery vehicles for human gene therapy. Three serotype capsids, AAV1, AAV2, and AAV9, have been approved for commercial use in patients, but they may not be suitable for all therapeutic contexts. Here, we describe a novel capsid identified in a human clinical sample by high-throughput, long-read sequencing. The capsid, which we have named AAVv66, shares high sequence similarity with AAV2. We demonstrate that compared to AAV2, AAVv66 exhibits enhanced production yields, virion stability, and CNS transduction. Unique structural properties of AAVv66 visualized by cryo-EM at 2.5-Å resolution, suggest that critical residues at the three-fold protrusion and at the interface of the five-fold axis of symmetry likely contribute to the beneficial characteristics of AAVv66. Our findings underscore the potential of AAVv66 as a gene therapy vector.

Date: 2020
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DOI: 10.1038/s41467-020-17047-1

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