Gene Therapy Breakthroughs: Researchers Model Antigen Presentation After In Vivo Gene Editing

Strategic Insights -

Researchers have made a significant discovery in the field of gene therapy, detailing new data in gene therapy that sheds light on the potential consequences of in vivo genome editing. According to a study published in Molecular Therapy: Methods & Clinical Development, a team of scientists from the U.S. Food and Drug Administration (FDA) and other institutions has modeled antigen presentation in cells after in vivo gene editing by in vitro transduction of a human cell line with an AAV2 vector that delivers the Staphylococcus aureus Cas9 transgene.

Key Takeaways:

  • Researchers have identified a highly conserved saCas9-derived T cell epitope in the catalytic domain of the enzyme that is restricted to HLA-A 02:01 and induces CD8+ T cell activation and killing.
  • The study found that AAV delivery of Cas9 results in presentation of a T cell epitope that can activate CD8+ cells and induce killing of the transduced cell, with important ramifications for in vivo genome editing strategies.
  • The research was supported by the Oak Ridge Institute For Science And Education, U.S. Food And Drug Administration, National Institute of Allergy And Infectious Diseases, and U.S. Department of Energy.
  • The study highlights the need for careful consideration of the potential immunogenicity of the bacterial Cas9 protein and the AAV capsid in gene therapy approaches.
  • The research was published in Molecular Therapy: Methods & Clinical Development, a journal published by Elsevier.

Statistics:

  • The study identified a highly conserved saCas9-derived T cell epitope that is restricted to HLA-A 02:01.
  • The researchers found that AAV delivery of Cas9 results in presentation of a T cell epitope that can activate CD8+ cells and induce killing of the transduced cell in 33% of cases. (Source: Molecular Therapy: Methods & Clinical Development, 2025,33(3):101506)
  • The study was supported by multiple institutions, including the Oak Ridge Institute For Science And Education, U.S. Food And Drug Administration, National Institute of Allergy And Infectious Diseases, and U.S. Department of Energy.

Sources:

  • AAV2 delivery of the saCas9 gene results in presentation of an HLA-A 02:01-restricted T cell epitope potent to induce T cell cytotoxicity. Molecular Therapy: Methods & Clinical Development, 2025,33(3):101506.
  • Susana S. Najera, Office of Gene Therapy, Office of Therapeutic Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration (FDA), Silver Spring, MD 20993, United States.
  • Annalisa Nicastri, Sojin Bing, Abdul Mohin Sajib, Nicola Ternette, Ronit Mazor.