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scAAV-mediated gene transfer of interleukin-1-receptor antagonist to synovium and articular cartilage in large mammalian joints

Gene Therapy volume 20, pages 670–677 (2013)Cite this article

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Abstract

With the long-term goal of developing a gene-based treatment for osteoarthritis (OA), we performed studies to evaluate the equine joint as a model for adeno-associated virus (AAV)-mediated gene transfer to large, weight-bearing human joints. A self-complementary AAV2 vector containing the coding regions for human interleukin-1-receptor antagonist (hIL-1Ra) or green fluorescent protein was packaged in AAV capsid serotypes 1, 2, 5, 8 and 9. Following infection of human and equine synovial fibroblasts in culture, we found that both were only receptive to transduction with AAV1, 2 and 5. For these serotypes, however, transgene expression from the equine cells was consistently at least 10-fold higher. Analyses of AAV surface receptor molecules and intracellular trafficking of vector genomes implicate enhanced viral uptake by the equine cells. Following delivery of 1 × 1011 vector genomes of serotypes 2, 5 and 8 into the forelimb joints of the horse, all three enabled hIL-1Ra expression at biologically relevant levels and effectively transduced the same cell types, primarily synovial fibroblasts and, to a lesser degree, chondrocytes in articular cartilage. These results provide optimism that AAV vectors can be effectively adapted for gene delivery to large human joints affected by OA.

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Acknowledgements

This study was supported by grants AR048566 and AR057422 from the NIH and the National Institute of Arthritis Musculoskeletal and Skin Diseases.

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Authors and Affiliations

  1. Department of Orthopaedics and Rehabilitation, University of Florida, Gainesville, FL, USA

    R S Watson, P P Levings, J D Kay, E Gouze, J-N Gouze, E A Dacanay & S C Ghivizzani

  2. Department of Large Animal Clinical Sciences, University of Florida, Gainesville, FL, USA

    T A Broome, B L Rice, A D Smith & P T Colahan

  3. Department of Molecular Genetics, University of Florida, Gainesville, FL, USA

    W W Hauswirth

  4. Department of Statistics and Actuarial Science, University of Central Florida, Orlando, FL, USA

    D M Nickerson

  5. Department of Infectious Diseases and Pathology, University of Florida, Gainesville, FL, USA

    M J Dark

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  1. R S Watson
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  7. E Gouze
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Correspondence to S C Ghivizzani.

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Competing interests

Dr Ghivizzani has an equity interest in Molecular Orthopaedics Inc., a company pursuing gene-based treatments for arthritic disease. All other authors declare no conflict of interest.

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Watson, R., Broome, T., Levings, P. et al. scAAV-mediated gene transfer of interleukin-1-receptor antagonist to synovium and articular cartilage in large mammalian joints. Gene Ther 20, 670–677 (2013). https://doi.org/10.1038/gt.2012.81

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