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

Author

Listed:
  • Hung-Lun Hsu

    (University of Massachusetts Medical School
    University of Massachusetts Medical School)

  • Alexander Brown

    (University of Massachusetts Medical School
    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
    University of Massachusetts Medical School)

  • Li Luo

    (University of Massachusetts Medical School
    Sichuan University)

  • Guangchao Xu

    (University of Massachusetts Medical School
    Sichuan University)

  • Jia Li

    (University of Massachusetts Medical School)

  • Lingzhi Ren

    (University of Massachusetts Medical School)

  • Qin Su

    (University of Massachusetts Medical School
    University of Massachusetts Medical School)

  • Dominic J. Gessler

    (University of Massachusetts Medical School
    University of Massachusetts Medical School)

  • Yuquan Wei

    (Sichuan University)

  • Phillip W. L. Tai

    (University of Massachusetts Medical School
    University of Massachusetts Medical School)

  • Andrei A. Korostelev

    (University of Massachusetts Medical School)

  • Guangping Gao

    (University of Massachusetts Medical School
    University of Massachusetts Medical School
    University of Massachusetts Medical School)

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.

Suggested Citation

  • 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. , 2020. "Structural characterization of a novel human adeno-associated virus capsid with neurotropic properties," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17047-1
    DOI: 10.1038/s41467-020-17047-1
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    Cited by:

    1. Shuang Luo & Hao Jiang & Qingwei Li & Yingfei Qin & Shiping Yang & Jing Li & Lingli Xu & Yan Gou & Yafei Zhang & Fengjiang Liu & Xiao Ke & Qiang Zheng & Xun Sun, 2024. "An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Zengpeng Han & Nengsong Luo & Wenyu Ma & Xiaodong Liu & Yuxiang Cai & Jiaxin Kou & Jie Wang & Lei Li & Siqi Peng & Zihong Xu & Wen Zhang & Yuxiang Qiu & Yang Wu & Chaohui Ye & Kunzhang Lin & Fuqiang X, 2023. "AAV11 enables efficient retrograde targeting of projection neurons and enhances astrocyte-directed transduction," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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