Lethal immunotoxicity in high-dose systemic AAV therapy

  • Mol Ther. 2023 Nov 1;31(11):3123-3126. doi: 10.1016/j.ymthe.2023.10.015.
Dongsheng Duan  1
Affiliations
  • 1. Department of Molecular Microbiology and Immunology and Department of Neurology, School of Medicine, Department of Biomedical Sciences, College of Veterinary Medicine, Department of Chemical and Biomedical Engineering, College of Engineering, University of Missouri, Columbia, MO 65212, USA. Electronic address: [email protected].
PMID: 37822079 DOI: 10.1016/j.ymthe.2023.10.015
Abstract

High-dose systemic gene therapy with adeno-associated virus (AAV) is in clinical trials to treat various inherited diseases. Despite remarkable success in spinal muscular atrophy and promising results in Other Diseases, fatality has been observed due to liver, kidney, heart, or lung failure. Innate and adaptive immune responses to the vector play a critical role in the toxicity. Host factors also contribute to patient death. This mini-review summarizes clinical findings and calls for concerted efforts from all stakeholders to better understand the mechanisms underlying lethality in AAV gene therapy and to develop effective strategies to prevent/treat high-dose systemic AAV-gene-therapy-induced immunotoxicity.

Keywords
AAV; ARDS; CRISPR; DMD; Duchenne muscular dystrophy; acute respiratory distress syndrome; adeno-associated virus; death; immunotoxicity; innate immune response; systemic gene therapy.