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Publications

Journal Article Review Ppublish

PubMed: 40156190 DOI: 10.1016/j.ymthe.2025.03.037

The curious case of AAV immunology.

Mol Ther 33(5):1946-1965

Authors: Allison M Keeler, Wei Zhan, Sanjay Ram, Katherine A Fitzgerald, Guangping Gao

Affiliations

  • Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; NeroNexus Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA; Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Division of Infectious Diseases and Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Genetic and Cellular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Microbiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.

Abstract

Immune responses to adeno-associated virus (AAV) have long been perplexing, from its first discovery to the latest clinical trials of recombinant AAV (rAAV) therapy. Wild-type AAV (wtAAV) does not cause any known disease, making it an ideal vector for gene therapy, as viral vectors retain virus-like properties. Although AAV stimulates only a mild immune response compared with other viruses, it is still recognized by the innate immune system and induces adaptive immune responses. B cell responses against both wtAAV and rAAV are robust and can hinder gene therapy applications and prevent redosing. T cell responses can clear transduced cells or establish tolerance against gene therapy. Immune responses to AAV gene therapy are influenced by many factors. Most clinical immunotoxicities that develop in response to gene therapies have emerged as higher doses of AAV vectors have been utilized and were not properly modeled in preclinical animal studies. Thus, several strategies have been undertaken to reduce or mitigate immune responses to AAV. While we have learned a considerable amount about how the immune system responds to AAV gene therapy since the discovery of AAV virus, it still remains a curious case that requires more investigation to fully understand.

MeSH

Cells, Genes, Viruses, Immune System, Immunity, Therapeutics, Genetic Therapy, Immunology