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

Front Immunol. 2024 Sep 27:15:1450858. doi: 10.3389/fimmu.2024.1450858. eCollection 2024.

Abstract

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, AAV5, AAV9, AAV7, 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 against some AAV types 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; binding antibodies; gene therapy; neuromuscular disease; neutralizing antibodies; seroprevalence; viral vector.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antibodies, Neutralizing* / blood
  • Antibodies, Neutralizing* / immunology
  • Antibodies, Viral* / blood
  • Antibodies, Viral* / immunology
  • Child
  • Child, Preschool
  • Dependovirus* / genetics
  • Dependovirus* / immunology
  • Female
  • Genetic Therapy
  • Genetic Vectors / genetics
  • Genetic Vectors / immunology
  • Humans
  • Male
  • Middle Aged
  • Neuromuscular Diseases* / immunology
  • Neuromuscular Diseases* / therapy
  • Seroepidemiologic Studies
  • Young Adult

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. XW received a stipend from the Chinese Scholarship Council. MV received funding from the Heimer Foundation for Muscle Research. We acknowledge support by the Open Access Publication Fund of the University of Duisburg-Essen.