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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Viral Immunology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1450858

Seroprevalence of binding and neutralizing antibodies against 18 adeno-associated virus types in patients with neuromuscular disorders

Provisionally accepted
Xiaoyan Wang Xiaoyan Wang 1Patrick J. Klann Patrick J. Klann 1,2*Ellen Wiedtke Ellen Wiedtke 3*Yumi Sano Yumi Sano 4*Nico Fischer Nico Fischer 3Lisa Schiller Lisa Schiller 3,5*Anna Elfert Anna Elfert 2*Anne-Katrin Güttsches Anne-Katrin Güttsches 2*Ute Weyen Ute Weyen 2*Dirk Grimm Dirk Grimm 3*Matthias Vorgerd Matthias Vorgerd 2*Wibke Bayer Wibke Bayer 6*
  • 1 Institute of Virology, University Hospital Essen, Essen, North Rhine-Westphalia, Germany
  • 2 BG-Kliniken Bergmannsheil, University Hospital, Heimer Institute for Muscle Research, Ruhr-University Bochum, Bochum, Germany
  • 3 Department of Infectious Diseases/Virology and Microbiology, Section Viral Vector Technologies BioQuant, Heidelberg University, Heidelberg, Germany, Heidelberg, Germany
  • 4 Department of Infectious Diseases/Virology and Microbiology, Section Viral Vector Technologies, BioQuant, Heidelberg University, Heidelberg, Baden-Württemberg, Germany
  • 5 Institute of Virology, TUM School of Medicine, Technical University of Munich/Helmholtz Centre Munich, Munich, Germany
  • 6 Institute for Virology, Essen University Hospital, Essen, Germany

The final, formatted version of the article will be published soon.

    High levels of pre-existing antibodies are a major challenge for the application of viral vectors since they can severely limit their efficacy. To identify promising candidates among adeno-associated virus (AAV) based vectors for future gene therapies for the treatment of hereditary neuromuscular disorders (NMDs), we investigated the antibody levels in sera from patients with NMDs against 18 AAV types, including 11 AAVs with wild-type capsids, 5 AAVs with peptide-modified capsids and 2 AAVs with shuffled capsids. With regard to the wild-type capsid AAVs, the lowest binding antibody levels were detected against AAV6, AAV5, AAV12 and AAV9, whereas the highest binding antibody levels were detected against AAV10, AAV8, AAV1, and AAV2. The lowest neutralizing antibody levels against wild-type AAVs were detected against AAV12, AAV9, AAV8 and AAV10, and the highest neutralizing antibody levels were detected against AAV13, AAV2 and AAV3. Interestingly, the influence of peptide modifications or shuffling of AAV capsids on antibody binding and AAV neutralization seemed to depend on the parental AAV. While the sex of the serum donors had no significant impact on binding or neutralizing antibody levels, we observed a trend to higher binding antibodies in older serum donors and a clear positive correlation of neutralizing antibody titers with the age of the serum donors. The disease status on the other hand did not have a meaningful impact on antibody levels, with no changes in AAV neutralization. Our data indicate that several wild-type or peptide-modified AAV may be good candidates for therapeutic application due to low pre-existing antibody levels, and that the age of potential recipients rather than their health status with regard to NMDs has the biggest impact on vector applicability.

    Keywords: adeno-associated virus, Viral vector, Gene Therapy, Neuromuscular Disease, seroprevalence, neutralizing antibodies, Binding antibodies

    Received: 18 Jun 2024; Accepted: 27 Aug 2024.

    Copyright: © 2024 Wang, Klann, Wiedtke, Sano, Fischer, Schiller, Elfert, Güttsches, Weyen, Grimm, Vorgerd and Bayer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Patrick J. Klann, Institute of Virology, University Hospital Essen, Essen, North Rhine-Westphalia, Germany
    Ellen Wiedtke, Department of Infectious Diseases/Virology and Microbiology, Section Viral Vector Technologies BioQuant, Heidelberg University, Heidelberg, Germany, Heidelberg, Germany
    Yumi Sano, Department of Infectious Diseases/Virology and Microbiology, Section Viral Vector Technologies, BioQuant, Heidelberg University, Heidelberg, 69117, Baden-Württemberg, Germany
    Lisa Schiller, Department of Infectious Diseases/Virology and Microbiology, Section Viral Vector Technologies BioQuant, Heidelberg University, Heidelberg, Germany, Heidelberg, Germany
    Anna Elfert, BG-Kliniken Bergmannsheil, University Hospital, Heimer Institute for Muscle Research, Ruhr-University Bochum, Bochum, Germany
    Anne-Katrin Güttsches, BG-Kliniken Bergmannsheil, University Hospital, Heimer Institute for Muscle Research, Ruhr-University Bochum, Bochum, Germany
    Ute Weyen, BG-Kliniken Bergmannsheil, University Hospital, Heimer Institute for Muscle Research, Ruhr-University Bochum, Bochum, Germany
    Dirk Grimm, Department of Infectious Diseases/Virology and Microbiology, Section Viral Vector Technologies BioQuant, Heidelberg University, Heidelberg, Germany, Heidelberg, Germany
    Matthias Vorgerd, BG-Kliniken Bergmannsheil, University Hospital, Heimer Institute for Muscle Research, Ruhr-University Bochum, Bochum, Germany
    Wibke Bayer, Institute for Virology, Essen University Hospital, Essen, Germany

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.