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Targeting recombinant adeno-associated virus vectors to enhance gene transfer to pancreatic islets and liver

Gene Therapy volume 10, pages 1551–1558 (2003)Cite this article

Abstract

Human pancreatic islet cells and hepatocytes represent the two most likely target cells for genetic therapy of type I diabetes. However, limits to the efficiency of rAAV serotype 2 (rAAV2)-mediated gene transfer have been reported for both of these cell targets. Here we report that nonserotype 2 AAV capsids can mediate more efficient transduction of islet cells, with AAV1 being the most efficient serotype in murine islets, suggesting that receptor abundance could be limiting. In order to test this, we generated rAAV particles that display a ligand (ApoE) that targets the low-density lipoprotein receptor, which is present on both of these cell types. The rAAV/ApoE viruses greatly enhanced the efficiency of transduction of both islet cells ex vivo and murine hepatocytes in vivo when compared to native rAAV2 serotype (220- and four-fold, respectively). The use of receptor-targeted rAAV particles may circumvent the lower abundance of receptors on certain nonpermissive cell types.

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Acknowledgements

We acknowledge Drs Sergei Zolotukhin and Jude Samulski for purified preparations of recombinant AAV serotypes. We also thank Dr Barry Byrne for the gift of pCMV-lucEYFP plasmid and Ms Amy Poirier for assistance with real-time PCR. These studies were supported by grants from the Juvenile Diabetes Research Foundation (to MA and TF), by the NIH (DK58327, HL51811, and HL59412), and by generous support from the Powell Endowment and Shands Hospital. Some of the authors (SL, SS, MA, NM, TRF) may be entitled to patent royalties for technology described herein.

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Authors and Affiliations

  1. Department of Pediatrics, Pathology, Medicine, and Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida Genetics Institute, Gainesville, FL, USA

    S A Loiler, T J Conlon, S Song, Q Tang, K H Warrington Jr, A Agarwal, M Kapturczak, C Li, C Ricordi, M A Atkinson, N Muzyczka & T R Flotte

  2. University of Miami Diabetics Research Center,

    S A Loiler, T J Conlon, S Song, Q Tang, K H Warrington Jr, A Agarwal, M Kapturczak, C Li, C Ricordi, M A Atkinson, N Muzyczka & T R Flotte

  3. University of North Carolina, Gene Therapy Center, Chapel Hill, NC, USA

    S A Loiler, T J Conlon, S Song, Q Tang, K H Warrington Jr, A Agarwal, M Kapturczak, C Li, C Ricordi, M A Atkinson, N Muzyczka & T R Flotte

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  1. S A Loiler
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  2. T J Conlon
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  8. C Li
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  10. M A Atkinson
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  11. N Muzyczka
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Loiler, S., Conlon, T., Song, S. et al. Targeting recombinant adeno-associated virus vectors to enhance gene transfer to pancreatic islets and liver. Gene Ther 10, 1551–1558 (2003). https://doi.org/10.1038/sj.gt.3302046

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