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Heparin-binding correlates with increased efficiency of AAV1- and AAV6-mediated transduction of striated muscle, but negatively impacts CNS transduction

Gene Therapy volume 20, pages 497–503 (2013)Cite this article

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Abstract

Gene delivery vectors derived from adeno-associated virus (AAV) have great potential as therapeutic agents. rAAV1 and rAAV6, efficiently target striated muscle, but the mechanisms that determine their tropism remain unclear. It is known that AAV6, but not AAV1, interacts with heparin-sulfate proteoglycans (HSPG). HSPGs are not primary receptors for AAV6, but heparin interactions may affect tissue tropism and transduction. To investigate these possibilities, we generated rAAV1 and rAAV6 capsids that do or do not bind heparin. We evaluated the transduction profile of these vectors in vivo across multiple routes of administration, and found that heparin-binding capability influences tissue transduction in striated muscle and neuronal tissues. Heparin-binding capsids transduce striated muscle more efficiently than non-binding capsids, via both intramuscular and intravenous injection. However, rAAV6 achieved greater muscle transduction than the heparin-binding rAAV1 variant, suggesting that there are additional factors that influence differences in transduction efficiency between AAV1 and AAV6. Interestingly, the opposite trend was found when vectors were delivered via intracranial injection. Non-binding vectors achieved robust and widespread gene expression, whereas transduction via heparin-binding serotypes was substantially reduced. These data indicate that heparin-binding capability is an important determinant of transduction that should be considered in the design of rAAV-mediated gene therapies.

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Acknowledgements

AA was supported by the Medical Scientist Training Program, and Achievement Rewards for College Scientists, as well as a National Research Service Award (NIH F30NS068005). This study was supported by NIH Grants AR40864, and AG33610 (to JSC).

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Authors and Affiliations

  1. Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA

    A L H Arnett, J Allen, E Finn & J S Chamberlain

  2. Medical Scientist Training Program, University of Washington, Seattle, WA, USA

    A L H Arnett & L R Beutler

  3. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    L R Beutler & R D Palmiter

  4. Department of Biochemistry, University of Washington, Seattle, WA, USA

    A Quintana, R D Palmiter & J S Chamberlain

  5. Department of Medicine, University of Washington, Seattle, WA, USA

    R D Palmiter & J S Chamberlain

  6. Department of Biochemistry, Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA

    R D Palmiter

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  1. A L H Arnett
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Correspondence to J S Chamberlain.

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Arnett, A., Beutler, L., Quintana, A. et al. Heparin-binding correlates with increased efficiency of AAV1- and AAV6-mediated transduction of striated muscle, but negatively impacts CNS transduction. Gene Ther 20, 497–503 (2013). https://doi.org/10.1038/gt.2012.60

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