Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

A largely random AAV integration profile after LPLD gene therapy

Nature Medicine volume 19, pages 889–891 (2013)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: AAV1-LPLS447X integration profile and persistence.

Similar content being viewed by others

References

  1. Asokan, A., Schaffer, D.V. & Samulski, R.J. Mol. Ther. 20, 699–708 (2012).

    Article  CAS  Google Scholar 

  2. Mingozzi, F. & High, K.A. Nat. Rev. Genet. 12, 341–355 (2011).

    Article  CAS  Google Scholar 

  3. High, K.A. & Aubourg, P. Methods Mol. Biol. 807, 429–457 (2011).

    Article  CAS  Google Scholar 

  4. Donsante, A. et al. Science 317, 477 (2007).

    Article  CAS  Google Scholar 

  5. Rosas, L.E. et al. Mol. Ther. 20, 2098–2110 (2012).

    Article  CAS  Google Scholar 

  6. Carpentier, A.C. et al. J. Clin. Endocrinol. Metab. 97, 1635–1644 (2012).

    Article  CAS  Google Scholar 

  7. Paruzynski, A. et al. Nat. Protoc. 5, 1379–1395 (2010).

    Article  CAS  Google Scholar 

  8. Schmidt, M. et al. Nat. Methods 4, 1051–1057 (2007).

    Article  CAS  Google Scholar 

  9. Nakai, H. et al. Nat. Genet. 34, 297–302 (2003).

    Article  CAS  Google Scholar 

  10. Inagaki, K. et al. J. Virol. 81, 11290–11303 (2007).

    Article  CAS  Google Scholar 

  11. Li, H. et al. Blood 117, 3311–3319 (2011).

    Article  CAS  Google Scholar 

  12. Nowrouzi, A. et al. Mol. Ther. 20, 1177–1186 (2012).

    Article  CAS  Google Scholar 

  13. Deyle, D.R. & Russell, D.W. Curr. Opin. Mol. Ther. 11, 442–447 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Wu, X., Luke, B.T. & Burgess, S.M. Virology 344, 292–295 (2006).

    Article  CAS  Google Scholar 

  15. Abel, U. et al. PLoS ONE 2, e570 (2007).

    Article  Google Scholar 

  16. Richly, E. et al. Mol. Biol. Evol. 21, 1081–1084 (2004).

    Article  CAS  Google Scholar 

  17. Hazkani-Covo, E. et al. PLoS Genet. 6, e1000834 (2010).

    Article  Google Scholar 

  18. Ramos, A. et al. Mitochondrion 11, 946–953 (2011).

    Article  CAS  Google Scholar 

  19. Calabrese, F.M. et al. BMC Bioinformatics 13 (suppl. 4), S15 (2012).

    Article  CAS  Google Scholar 

  20. Yu, H. et al. Proc. Natl. Acad. Sci. USA 109, E1238–E1247 (2012).

    Article  CAS  Google Scholar 

  21. Zhang, Z., Schwartz, S., Wagner, L. & Miller, W. J. Comput. Biol. 7, 203–214 (2000).

    Article  CAS  Google Scholar 

  22. Suzuki, T. et al. Nat. Genet. 32, 166–174 (2002).

    Article  CAS  Google Scholar 

  23. Wu, T.D. et al. Bioinformatics 26, 873–881 (2010).

    Article  CAS  Google Scholar 

  24. Li, H. et al. Bioinformatics 25, 2078–2079 (2009).

    Article  Google Scholar 

  25. Robinson, J.T. et al. Nat. Biotechnol. 29, 24–26 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stuart G Beattie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raffaele Fronza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard van Logtenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Florence Salmon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sabine Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stephan Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ali Nowrouzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hanno Glimm
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christof von Kalle
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Harald Petry
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Daniel Gaudet
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Manfred Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research