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Adeno-associated virus capsid assembly is divergent and stochastic

Author

Listed:
  • Tobias P. Wörner

    (University of Utrecht
    Netherlands Proteomics Center)

  • Antonette Bennett

    (Department of Biochemistry and Molecular Biology, Center for Structural Biology, the McKnight Brain Institute)

  • Sana Habka

    (University of Utrecht
    Netherlands Proteomics Center)

  • Joost Snijder

    (University of Utrecht
    Netherlands Proteomics Center)

  • Olga Friese

    (Biotherapeutics Pharmaceutical Sciences, Pfizer WRDM)

  • Thomas Powers

    (Biotherapeutics Pharmaceutical Sciences, Pfizer WRDM)

  • Mavis Agbandje-McKenna

    (Department of Biochemistry and Molecular Biology, Center for Structural Biology, the McKnight Brain Institute)

  • Albert J. R. Heck

    (University of Utrecht
    Netherlands Proteomics Center)

Abstract

Adeno-associated viruses (AAVs) are increasingly used as gene therapy vectors. AAVs package their genome in a non-enveloped T = 1 icosahedral capsid of ~3.8 megaDalton, consisting of 60 subunits of 3 distinct viral proteins (VPs), which vary only in their N-terminus. While all three VPs play a role in cell-entry and transduction, their precise stoichiometry and structural organization in the capsid has remained elusive. Here we investigate the composition of several AAV serotypes by high-resolution native mass spectrometry. Our data reveal that the capsids assemble stochastically, leading to a highly heterogeneous population of capsids of variable composition, whereby even the single-most abundant VP stoichiometry represents only a small percentage of the total AAV population. We estimate that virtually every AAV capsid in a particular preparation has a unique composition. The systematic scoring of the simulations against experimental native MS data offers a sensitive new method to characterize these therapeutically important heterogeneous capsids.

Suggested Citation

  • Tobias P. Wörner & Antonette Bennett & Sana Habka & Joost Snijder & Olga Friese & Thomas Powers & Mavis Agbandje-McKenna & Albert J. R. Heck, 2021. "Adeno-associated virus capsid assembly is divergent and stochastic," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21935-5
    DOI: 10.1038/s41467-021-21935-5
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