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A largely random AAV integration profile after LPLD gene therapy

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Abstract

The clinical application of adeno-associated virus vectors (AAVs) is limited because of concerns about AAV integration–mediated tumorigenicity. We performed integration-site analysis after AAV1-LPLS447X intramuscular injection in five lipoprotein lipase–deficient subjects, revealing random nuclear integration and hotspots in mitochondria. We conclude that AAV integration is potentially safe and that vector breakage and integration may occur from each position of the vector genome. Future viral integration-site analyses should include the mitochondrial genome.

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Figure 1: AAV1-LPLS447X integration profile and persistence.

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Acknowledgements

This study has been supported by funds from the European Commission project with short name AIPGENE (grant FP7-HEALTH-2010-261506).

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Author notes

  1. Stuart G Beattie

    Present address: Present address: Genetics, University College London Institute of Ophthalmology, London, UK.,

  2. Christine Kaeppel, Stuart G Beattie and Raffaele Fronza: These authors contributed equally to this work.

Authors and Affiliations

  1. National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany

    Christine Kaeppel, Raffaele Fronza, Ali Nowrouzi, Hanno Glimm, Christof von Kalle & Manfred Schmidt

  2. uniQure, Amsterdam, The Netherlands

    Stuart G Beattie, Richard van Logtenstein, Florence Salmon & Harald Petry

  3. Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany

    Sabine Schmidt & Stephan Wolf

  4. Department of Medicine, ECOGENE-21 Clinical Research Center, Université de Montréal, Chicoutimi, Québec, Canada

    Daniel Gaudet

Authors
  1. Christine Kaeppel
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  2. Stuart G Beattie
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  3. Raffaele Fronza
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  4. Richard van Logtenstein
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  5. Florence Salmon
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  6. Sabine Schmidt
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  7. Stephan Wolf
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  8. Ali Nowrouzi
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  9. Hanno Glimm
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  10. Christof von Kalle
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  11. Harald Petry
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  12. Daniel Gaudet
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  13. Manfred Schmidt
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Contributions

C.K., S.G.B. and R.F. took part in setting up the experimental design, performed experiments and data mining, and wrote the manuscript. R.v.L., F.S., H.P. and D.G. provided valuable material and intellectual input. A.N., H.G. and C.v.K. provided valuable discussion and conceptual advice. S.S. and S.W. provided valuable discussion and performed sequencing. M.S. set up the research concept and experimental design, and wrote the manuscript.

Corresponding author

Correspondence to Manfred Schmidt.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Tables 1–5 and Supplementary Note (PDF 491 kb)

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Kaeppel, C., Beattie, S., Fronza, R. et al. A largely random AAV integration profile after LPLD gene therapy. Nat Med 19, 889–891 (2013). https://doi.org/10.1038/nm.3230

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  • DOI: https://doi.org/10.1038/nm.3230

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