Contaminating plasmid sequences and disrupted vector genomes in the liver following adeno-associated virus gene therapy
Year: 2026
Type: article
Study design: Case Report
Abstract: Adeno-associated viruses (AAVs) are common vectors in gene therapy but can frequently cause liver complications in patients. The mechanisms underlying AAV-related liver toxicity remain poorly understood, posing challenges for effective prevention and intervention. Here we conducted a case study of a child with spinal muscular atrophy type 1 experiencing substantial hepatitis after receiving onasemnogene abeparvovec, undertaking long- and short-read metagenomic sequencing of liver tissue. We identified manufacturing plasmid sequences with complex structures and recombination. Vector genomes had extensive disruption and concatemerization as well as numerous vector-human fusion junctions. We also identified human betaherpesvirus 6B in the liver. Further work and investigation of more patients is needed to establish whether the presence of manufacturing plasmid sequences or helper viruses contribute to the formation of these complex concatemeric DNA structures in the liver, and whether these are a factor in the development of liver toxicity after AAV gene therapy.
Source: Nature Medicine
Authors: Sarah Buddle, Li-An K. Brown, Sofia Morfopoulou, Oscar Enrique Torres Montaguth, Mariacristina Scoto, Vanessa Herder, Anil Dhawan, Julianne R. Brown, Laura Atkinson, Angelika Kopec, Dee Davis, Nathaniel Storey, Luis Campos, Neil Sebire, Hannah Macpherson, Jasmaine Lee, Richard Orton, Giovanni Baranello, Patawee Asamaphan, Georgios Ilia, Rajvinder Karda, Holly Belfield, ISARIC4C Investigators, Malcolm Gracie Semple, J. Kenneth Baillie, John Counsell, Simon N. Waddington, Emma C. Thomson, Francesco Muntoni, Judith Breuer
Institutions: University College London, Great Ormond Street Hospital, National Institute for Health and Care Research, NIHR Great Ormond Street Hospital Biomedical Research Centre, MRC University of Glasgow Centre for Virus Research, University of Glasgow, King's College Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, UCL Queen Square Institute of Neurology, University of Liverpool, Alder Hey Children's NHS Foundation Trust, Alder Hey Children's Hospital, Roslin Institute, Edinburgh Royal Infirmary, Centre for Inflammation Research, University of Edinburgh
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
OpenAlex ID: W7124440284