Evidence map›Paper›PMID 41545588›Full record

ArticleNature medicine2026

Contaminating plasmid sequences and disrupted vector genomes in the liver following adeno-associated virus gene therapy.

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 and 18 more

Abstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

10 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Article
  6. Article
  7. Article
  8. Article
  9. Review
  10. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors.

Sarah Buddle *Infection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK.ORCID http://orcid.org/0000-0002-4738-9469
Li-An K Brown *Infection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK.ORCID http://orcid.org/0000-0002-8261-0288
Sofia MorfopoulouInfection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK.
Oscar Enrique Torres MontaguthInfection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK.
Mariacristina ScotoDubowitz Neuromuscular Centre, University College London Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, London, UK.
Vanessa HerderMedical Research Council-University of Glasgow Centre for Virus Research, Glasgow, UK.ORCID http://orcid.org/0000-0003-4814-1382
Anil DhawanPaediatric Liver GI and Nutrition Centre, King's College Hospital, London, UK.
Julianne R BrownDepartment of Microbiology, Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Laura AtkinsonDepartment of Microbiology, Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Angelika KopecDepartment of Microbiology, Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Dee DavisDepartment of Microbiology, Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Nathaniel StoreyDepartment of Microbiology, Virology and Infection Control, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.ORCID http://orcid.org/0000-0001-5942-4674
Luis CamposHistopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.ORCID http://orcid.org/0000-0002-4317-0013
Neil SebireHistopathology Department, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Hannah MacphersonLong Read Sequencing Facility, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.ORCID http://orcid.org/0000-0002-9535-4025
Jasmaine LeeLong Read Sequencing Facility, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK.
Richard OrtonMedical Research Council-University of Glasgow Centre for Virus Research, Glasgow, UK.
Giovanni BaranelloDubowitz Neuromuscular Centre, University College London Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, London, UK.ORCID http://orcid.org/0000-0003-4871-6692
Patawee AsamaphanMedical Research Council-University of Glasgow Centre for Virus Research, Glasgow, UK.
Georgios IliaMedical Research Council-University of Glasgow Centre for Virus Research, Glasgow, UK.ORCID http://orcid.org/0009-0003-4109-5966
Rajvinder KardaEGA Institute for Women's Health, University College London, London, UK.ORCID http://orcid.org/0000-0001-9821-483X
Holly BelfieldCritical Care Research Team, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
ISARIC4C Investigators
John CounsellResearch Department of Targeted Intervention, Division of Surgery and Interventional Science, University College London, London, UK.ORCID http://orcid.org/0000-0001-9208-101X
Simon N WaddingtonEGA Institute for Women's Health, University College London, London, UK.ORCID http://orcid.org/0000-0003-4970-4730
Emma C ThomsonMedical Research Council-University of Glasgow Centre for Virus Research, Glasgow, UK.ORCID http://orcid.org/0000-0003-1482-0889
Francesco MuntoniDubowitz Neuromuscular Centre, University College London Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, London, UK.ORCID http://orcid.org/0000-0002-9102-5232
Judith BreuerInfection, Immunity and Inflammation Department, Great Ormond Street Institute of Child Health, University College London, London, UK. j.breuer@ucl.ac.uk.ORCID http://orcid.org/0000-0001-8246-0534

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

DependovirusGenetic TherapyGenetic VectorsGenome, ViralLiverMuscular Atrophy, SpinalPlasmidsGene Therapy AgentsHumansRecombinant Fusion Proteinsonasemnogene abeparvovecRecombinant Fusion Proteins

Identifiers

PMID41545588
PMCPMC12920116

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.