Methods for Gene Transfer to Synovium

  • Richard Kang
  • Paul D. Robbins
  • Christopher H. Evans
Part of the Methods in Molecular Medicine book series (MIMM, volume 7)


Development of methods for gene transfer to synoviocytes was borne from the idea that gene therapy could be used to more effectively treat rheumatoid arthritis (EU) and other joint disorders (1). Current pharmaceutical modalities in use against RA have limited effectiveness because of problems related to inefficient targeting of drugs to the joint, as well as inefficacies of the drugs themselves. Drug delivery to the joint by traditional oral, iv, and intramuscular routes, depends on passive diffusion of the drug from the synovial vasculature into the joint space (2). Thus, high systemic concentrations of the drug are necessary to achieve therapeutic intra-articular drug levels; in chronic RA, perfusion of the synovium may be compromised (3), driving required systemic drug levels even higher. This is of major concern, as the pharmaceuticals used to treat this disease are associated with serious side effects. Further compounding these problems is the chronic nature of RA, which requires lifelong treatment with high dosages of these drugs.


Joint Space Synovial Tissue Patellar Tendon Medial Collateral Ligament Synovial Fibroblast 
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  1. 1.
    Bandara, G., Robbins, P. D, Georgescu, H. I., Mueller, G. M, Glorioso, J. C., and Evans, C. H. (1992) Gene transfer to synoviocytes:prospects for gene treatment of arthritis. DNA Cell Biol. 11, 227–231.PubMedCrossRefGoogle Scholar
  2. 2.
    Hung, G. L. and Evans, C. H. (1994) Synovium, in Knee Surgery (Fu, F. H, Harner, C. D., and Vince, K. G., eds.), Williams and Wilkins, Baltimore, MD, pp 141–154.Google Scholar
  3. 3.
    Stevens, C. R., Blake, D. R., Merry, P., Revel, P. A., and Levick, J. R. (1991) A comparative study by morphometry of the microvasculature in normal and rheumatoid synovium. Arthritis Rheum 36, 1508–1513.Google Scholar
  4. 4.
    Evans, C. H. and Robbins, P. D. (1994) Prospects for treating arthritis by gene therapy. J. Rheum. 21, 779–782.PubMedGoogle Scholar
  5. 5.
    Levick, J. R. (1981) Permeability of rheumatoid and normal human synovium to specific plasma proteins. Arthritis Rheum. 24, 1550–1560.PubMedCrossRefGoogle Scholar
  6. 6.
    Wallis, W. J., Simkin, P. A., and Nelp, W. B. (1987) Protein traffic in human synovial effusions. Arthritis Rheum. 30, 57–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Evans, C. H. and Robbins, P. D. (1994) Gene therapy for arthritis, in Gene Therapeutics. Methods and Applications of Direct Gene Transfer (Wolff, J. A., ed.), Birkhauser, Boston, pp. 320–343.Google Scholar
  8. 8.
    Nita, I., Galea-Lauri, J., Georgescu, H. I., Mueller, G., Gao, X., Huang, L., Glorioso, J. C., Robbins, P. D., and Evans, C. H. (1994) Direct gene transfer to synovium. Transactions of the 40th Annual Meeting of the Orthopaedic Research Society 19, 479.Google Scholar
  9. 9.
    Bandara, G., Mueller, G. M., Galea-Lauri, J., Tindal, M. H., Georgescu, H. I., Suchanek, M. K., Hung, G. L., Glorioso, J. C., Robbins, P. D., and Evans, C. H. (1993) Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl. Acad. Sci. USA 90, 10,764–10,768.PubMedCrossRefGoogle Scholar
  10. 10.
    Hung, G L., Robbins, P. D., and Evans, C. H. (1994) Synovial Cell Transplantation, in Methods in Cell Transplantation (Ricordi, C., ed.), R. G. Landes, pp.227–234.Google Scholar
  11. 11.
    Revell, P. A. (1989) Synovial lining cells. Rheumatol Int. 9, 49–51.PubMedCrossRefGoogle Scholar
  12. 12.
    Wilkinson, L. S., Pitsillides, A. A., Worrall, J. J., and Edwards, J. C. W. (1992) Light microscopic characterization of the fibroblast-like synovial intimal cell (synoviocyte). Arthritis Rheum. 35, 1179–1184.PubMedCrossRefGoogle Scholar
  13. 13.
    Stevens, C. R., Mapp, P. I., and Revell, P. A. (1988) A monoclonal antibody (MAb 67) marks type B synoviocytes. Rheumatol Int. 10, 103–106.CrossRefGoogle Scholar
  14. 14.
    Kinsella, T. D., Baum, J., and Ziff, M. (1970) Studies of isolated synovial lining cells of rheumatoid and non-rheumatoid synovial membranes Arthritis Rheum 13, 734–742.PubMedCrossRefGoogle Scholar
  15. 15.
    Evans, C. H., Bandara, G., Mueller, G., Robbins, P. D., Glorioso, J. C., and Georgescu, H. I. (1992) Synovial cell transplants for gene transfer to joints. Transplantation Proc. 24, 2966.Google Scholar
  16. 16.
    Evans, C. H., Mazzocchi, R. A., Nelson, D. D., and Rubash, H. E. (1984) Experimental arthritis induced by intraarticular injection of allogeneic cartilaginous particles into rabbit knees, Arthritis Rheum. 27, 200–207.PubMedCrossRefGoogle Scholar
  17. 17.
    Olson, E. J., Kang, J. D., Fu, F. H., Georgescu, H. I., Mason, C. G., and Evans, C. H. (1988) The biochemical and histological effects of artificial ligament wear particles: in vitro and in vivo studies. Am J. Sports Med. 16, 558–570.PubMedCrossRefGoogle Scholar
  18. 18.
    Haynes, B. F., Hale, L. P., Patton, K. L., Martin, M. E., and McCallum, R. M. (1991) Measurement of an adhesion molecule as an indicator of inflammatory disease activity: up-regulation of the receptor for hyaluronan (CD44) in rheumatoid arthritis. Arthritis Rheum. 34, 1436–1443.Google Scholar
  19. 19.
    Galea-Lauri, J., Wilkinson, J. M., and Evans, C. H. (1993) Characterization of monoclonal antibodies against CD44: evidence of a role for CD44 in modulating synovial metabolism. Mol. Immunol. 30, 1383–1392.PubMedCrossRefGoogle Scholar
  20. 20.
    Hung, G. L., Galea-Lauri, J., Mueller, G. M., Georgescu, H. I., Larkin, L. A., Suchanek, M. K., Tindal, M. H., Robbins, P. D., and Evans, C. H. (1994) Suppression of intra-articular responses to inerleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium. Gene Ther. 1, 64–69.PubMedGoogle Scholar
  21. 21.
    Evans, C. H. and Robbins, P. D. (1994) The interleukin-1 receptor antagonist and its delivery by gene transfer. Receptor 4, 9–15.PubMedGoogle Scholar
  22. 22.
    Ohtani, K. and Evans, C. H. Manuscript in preparation.Google Scholar
  23. 23.
    Ohashi, T., Boggs, S., Robbins, P. D., Bahnson, A., Patrene, K., Wei, F. S., Wei, J F., Li, J, Lucht, L., Fei, Y., Clark, S, Kimak, M., He, H., Mowery-Rushton, P., and Barranger, J. A (1992) Efficient transfer and sustained high expression of the human glucocerebrosidase gene in mice and their functional macrophages following transplantation of bone marrow transduced by a retroviral vector. Proc. Natl. Acad. Sci. USA 89, 11,332–11,336.PubMedCrossRefGoogle Scholar
  24. 24.
    Dranoff, G., Jaffee, E., Lazenby, A, Golumbek, P., Levitsky, H., Brose, K., Jackson, V., Hamada, H., Pardoll, D., and Mulligan, R. C. (1993) Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl. Acad. Sci. USA 90, 3539–3543.PubMedCrossRefGoogle Scholar
  25. 25.
    Price, J., Turner, D., and Cepko, C (1987) Lineage analysis in the vertebrate nervous system by retrovirus-mediated gene transfer. Proc Natl Acad. Sci. USA 84, 156–160.PubMedCrossRefGoogle Scholar
  26. 26.
    Farndale, R. W., Buttle, D. J., and Barrett A. J. (1986) Improved quantitation and discrimination of sulfated glycosaminoglycans by use of methylene blue. Biochem. Biophys Acta 883, 173–177.PubMedCrossRefGoogle Scholar
  27. 27.
    Sanes, J R., Rubenstein, J. L. R., and Nicolas, J. F (1986) Use of a recombinant retrovirus to study post-implantation cell lineage in mouse embryos EMBO J 5, 3133–3142.PubMedGoogle Scholar
  28. 28.
    Green, W. T., Jr. (1971) Behavior of articular chondrocytes. Clin Orthop. 75, 248–260.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 1997

Authors and Affiliations

  • Richard Kang
    • 1
  • Paul D. Robbins
    • 2
  • Christopher H. Evans
    • 3
  1. 1.Orthopedic SurgeryUniversity of Pittsburgh School of MedicinePittsburgh
  2. 2.Department of Molecular Genetics and BiochemistryUniversity of Pittsburgh
  3. 3.Department of Molecular Genetics and BiochemistryUniversity of Pittsburgh Medical CenterPittsburgh

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