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Gene therapy for rheumatoid arthritis

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Abstract

Rheumatoid arthritis (RA) is a painful chronic disorder. Conventional therapies are palliative, not curative. Advances in the understanding of the pathophysiology of RA have led to the development of new therapeutic strategies, including gene therapy. Multiple studies in several different animal models provide proof supporting the use of gene therapy in arthritis. A phase I clinical trial has already been performed successfully on nine women with end-stage RA in the United States, and two other trials are in progress. Limited duration of gene expression impedes the development of a clinically useful genetic treatment for arthritis.

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References and Recommended Reading

  1. Moreland LW, Heck LW Jr, Koopman WJ: Biologic agents for treating rheumatoid arthritis. Concepts and progress. Arthritis Rheum 1997, 40:397–409.

    Article  PubMed  CAS  Google Scholar 

  2. Evans CH, Ghivizzani SC, Kang R, et al.: Gene therapy for rheumatic diseases. Arthritis Rheum 1999, 42:1–16. This paper is a comprehensive and detailed review of the entire field of gene therapy.

    Article  PubMed  CAS  Google Scholar 

  3. Robbins PD, Ghivizzani SC: Viral vectors for gene therapy. Pharmacol Ther 1998, 80:35–47.

    Article  PubMed  CAS  Google Scholar 

  4. Ghivizzani SC, Lechman ER, Tio C, et al.: Direct retrovirusmediated gene transfer to the synovium of the rabbit knee: implications for arthritis gene therapy. Gene Ther 1997, 4:977–982.

    Article  PubMed  CAS  Google Scholar 

  5. Pan RY, Chen SL, Xiao X, et al.: Therapy and prevention of arthritis by recombinant adeno-associated virus vector with delivery of interleukin-1 receptor antagonist. Arthritis Rheum 2000, 43:289–297. This paper reports the unexpected, but potentially important, finding that gene expression in joints can be reactivated by inflammatory stimuli.

    Article  PubMed  CAS  Google Scholar 

  6. Goater J, Muller R, Kollias G, et al.: Empirical advantages of adeno associated viral vectors in vivo gene therapy for arthritis. J Rheumatol 2000, 27:983–989.

    PubMed  CAS  Google Scholar 

  7. Oligino TJ, Yao Q, Wang S, et al.: Intra-articular expression of the IL-1Ra gene following direct delivery with an adenoassociated virus vector. Gene Ther, in press.

  8. Nita I, Ghivizzani SC, Galea-Lauri J, et al.: Direct gene delivery to synovium. An evaluation of potential vectors in vitro and in vivo. Arthritis Rheum 1996, 39:820–828.

    Article  PubMed  CAS  Google Scholar 

  9. Oligino T, Ghivizzani S, Wolfe D, et al.: Intra-articular delivery of a herpes simplex virus IL-1Ra gene vector reduces inflammation in a rabbit model of arthritis. Gene Ther 1999, 6:1713–1720.

    Article  PubMed  CAS  Google Scholar 

  10. Krisky DM, Marconi PC, Oligino TJ, et al.: Development of herpes simplex virus replication-defective multigene vectors for combination gene therapy applications. Gene Ther 1998, 5:1517–1530.

    Article  PubMed  CAS  Google Scholar 

  11. Chernajovsky Y, Adams G, Podhajcer OL, et al.: Inhibition of transfer of collagen-induced arthritis into SCID mice by ex vivo infection of spleen cells with retroviruses expressing soluble tumor necrosis factor receptor. Gene Ther 1995, 2:731–735.

    PubMed  CAS  Google Scholar 

  12. Chernajovsky Y, Adams G, Triantaphyllopoulos K, et al.: Pathogenic lymphoid cells engineered to express TGF beta 1 ameliorate disease in a collagen-induced arthritis model. Gene Ther 1997, 4:553–559.

    Article  PubMed  CAS  Google Scholar 

  13. Ma Y, Thornton S, Duwel LE, et al.: Inhibition of collageninduced arthritis in mice by viral IL-10 gene transfer. J Immunol 1998, 161:1516–1524.

    PubMed  CAS  Google Scholar 

  14. Song XY, Gu M, Jin WW, et al.: Plasmid DNA encoding transforming growth factor-beta1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model. J Clin Invest 1998, 101:2615–2621.

    PubMed  CAS  Google Scholar 

  15. Le CH, Nicolson AG, Morales A, Sewell KL: Suppression of collagen-induced arthritis through adenovirus-mediated transfer of a modified tumor necrosis factor alpha receptor gene. Arthritis Rheum 1997, 40:1662–1669.

    Article  PubMed  CAS  Google Scholar 

  16. Evans CH, Robbins PD: Pathways to gene therapy in rheumatoid arthritis. Curr Opin Rheumatol 1996, 8:230–234.

    Article  PubMed  CAS  Google Scholar 

  17. Evans CH, Ghivizzani SC, Robbins PD: Blocking cytokines with genes. J Leukoc Biol 1998, 64:55–61.

    PubMed  CAS  Google Scholar 

  18. Evans CH, Robbins PD: Gene therapy of arthritis. Intern Med 1999, 38:233–239.

    PubMed  CAS  Google Scholar 

  19. Robbins PD, Evans CH, Chernajovsky Y: Gene therapy for rheumatoid arthritis. Springer Semin Immunopathol 1998, 20:197–209.

    Article  PubMed  CAS  Google Scholar 

  20. Evans CH, Robbins PD, Ghivizzani SC, et al.: Clinical trial to assess the safety, feasibility, and efficacy of transferring a potentially anti-arthritic cytokine gene to human joints with rheumatoid arthritis. Hum Gene Ther 1996, 7:1261–1280.

    PubMed  CAS  Google Scholar 

  21. Bandara G, Mueller GM, Galea-Lauri J, et al.: Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci U S A 1993, 90:10764–10768.

    Article  PubMed  CAS  Google Scholar 

  22. Bakker AC, Joosten LA, Arntz OJ, et al.: Prevention of murine collagen-induced arthritis in the knee and ipsilateral paw by local expression of human interleukin-1 receptor antagonist protein in the knee. Arthritis Rheum 1997, 40:893–900.

    Article  PubMed  CAS  Google Scholar 

  23. Hung GL, Galea-Lauri J, Mueller GM, et al.: Suppression of intra-articular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium. Gene Ther 1994, 1:64–69.

    PubMed  CAS  Google Scholar 

  24. Makarov SS, Olsen JC, Johnston WN, et al.: Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA. Proc Natl Acad Sci U S A 1996, 93:402–406.

    Article  PubMed  CAS  Google Scholar 

  25. Otani K, Nita I, Macaulay W, et al.: Suppression of antigeninduced arthritis in rabbits by ex vivo gene therapy. J Immunol 1996, 156:3558–3562.

    PubMed  CAS  Google Scholar 

  26. Muller-Ladner U, Roberts CR, Franklin BN, et al.: Human IL-1Ra gene transfer into human synovial fibroblasts is chondroprotective. J Immunol 1997, 158:3492–3498.

    PubMed  CAS  Google Scholar 

  27. Ghivizzani SC, Lechman ER, Kang R, et al.: Direct adenovirusmediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects. Proc Natl Acad Sci U S A 1998, 95:4613–4618. This study reports for the first time bilateral improvement of arthritis after local gene therapy in one knee. These observations suggest new beneficial mechanisms triggered by gene therapy.

    Article  PubMed  CAS  Google Scholar 

  28. Quattrocchi E, Walmsley M, Browne K, et al.: Paradoxical effects of adenovirus-mediated blockade of TNF activity in murine collagen-induced arthritis. J Immunol 1999, 163:1000–1009.

    PubMed  CAS  Google Scholar 

  29. Tomita T, Takeuchi E, Tomita N, et al.: Suppressed severity of collagen-induced arthritis by in vivo transfection of nuclear factor kappaB decoy oligodeoxynucleotides as a gene therapy. Arthritis Rheum 1999, 42:2532–2542.

    Article  PubMed  CAS  Google Scholar 

  30. Miagkov AV, Kovalenko DV, Brown CE, et al.: NF-kappaB activation provides the potential link between inflammation and hyperplasia in the arthritic joint. Proc Natl Acad Sci U S A 1998, 95:13859–13864. This paper highlights the importance of NF-kappaB as a target for gene therapy.

    Article  PubMed  CAS  Google Scholar 

  31. Zhang HG, Huang N, Liu D, et al.: Gene therapy that inhibits nuclear translocation of nuclear factor kappaB results in tumor necrosis factor alpha-induced apoptosis of human synovial fibroblasts. Arthritis Rheum 2000, 43:1094–1105.

    Article  PubMed  CAS  Google Scholar 

  32. Makarov SS, Johnston WN, Olsen JC, et al.: NF-kappa B as a target for anti-inflammatory gene therapy: suppression of inflammatory responses in monocytic and stromal cells by stable gene transfer of I kappa B alpha cDNA. Gene Ther 1997, 4:846–852.

    Article  PubMed  CAS  Google Scholar 

  33. Shiozawa S, Shimizu K, Tanaka K, Hino K: Studies on the contribution of c-fos/AP-1 to arthritic joint destruction. J Clin Invest 1997, 99:1210–1216.

    PubMed  CAS  Google Scholar 

  34. Wakisaka S, Suzuki N, Saito N, et al.: Possible correction of abnormal rheumatoid arthritis synovial cell function by jun D transfection in vitro. Arthritis Rheum 1998, 41:470–481.

    Article  PubMed  CAS  Google Scholar 

  35. Takayanagi H, Juji T, Miyazaki T, et al.: Suppression of arthritic bone destruction by adenovirus-mediated csk gene transfer to synoviocytes and osteoclasts. J Clin Invest 1999, 104:137–146. This paper identifies a new target for preserving bone in rheumatoid arthritis.

    PubMed  CAS  Google Scholar 

  36. Lubberts E, Joosten LA, van Den Bersselaar L, et al.: Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction. J Immunol 1999, 163:4546–4556. This paper reports the unusual finding that IL-4 potently protects bone and cartilage while increasing synovial inflammation.

    PubMed  CAS  Google Scholar 

  37. Boyle DL, Nguyen KH, Zhuang S, et al.: Intra-articular IL-4 gene therapy in arthritis: anti-inflammatory effect and enhanced Th2 activity. Gene Ther 1999, 6:1911–1918.

    Article  PubMed  CAS  Google Scholar 

  38. Kim SH, Evans CH, Kim S, et al.: Gene therapy for established murine collagen-induced arthritis by local and systemic adenovirus-mediated delivery of interleukin-4. Arthritis Res 2000, 2(4):293–302.

    Article  PubMed  CAS  Google Scholar 

  39. Apparailly F, Verwaerde C, Jacquet C, et al.: Adenovirusmediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis. J Immunol 1998, 160:5213–5220.

    PubMed  CAS  Google Scholar 

  40. Whalen JD, Lechman EL, Carlos CA, et al.: Adenoviral transfer of the viral IL-10 gene periarticularly to mouse paws suppresses development of collagen-induced arthritis in both injected and uninjected paws. J Immunol 1999, 162:3625–3632.

    PubMed  CAS  Google Scholar 

  41. Lechman ER, Jaffurs D, Ghivizzani SC, et al.: Direct adenoviral gene transfer of viral IL-10 to rabbit knees with experimental arthritis ameliorates disease in both injected and contralateral control knees. J Immunol 1999, 163:2202–2208.

    PubMed  CAS  Google Scholar 

  42. Muller-Ladner U, Evans CH, Franklin BN, et al.: Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model. Arthritis Rheum 1999, 42:490–497. Using an ingenious synoviocytes implanted in severe combined immunodeficient model, this paper shows that IL-10 gene transfer to human rheumatoid synovium potently inhibits invasion of cartilage. Oddly, the TNFsR gene was without effect.

    Article  PubMed  CAS  Google Scholar 

  43. Bessis N, Boissier MC, Ferrara P, et al.: Attenuation of collageninduced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13. Eur J Immunol 1996, 26:2399–2403.

    Article  PubMed  CAS  Google Scholar 

  44. Zhang HG, Liu D, Heike Y, et al.: Induction of specific T-cell tolerance by adenovirus-transfected, Fas ligand-producing antigen presenting cells. Nat Biotechnol 1998, 16:1045–1049. This paper reports an ingenious method for achieving immune tolerance using antigen-presenting cells transduced with Fas ligand.

    Article  PubMed  CAS  Google Scholar 

  45. Zhang HG, Su X, Liu D, et al.: Induction of specific T cell tolerance by Fas ligand-expressing antigen-presenting cells. J Immunol 1999, 162:1423–1430.

    PubMed  CAS  Google Scholar 

  46. Rabinovich GA, Daly G, Dreja H, et al.: Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis. J Exp Med 1999, 190:385–398.

    Article  PubMed  CAS  Google Scholar 

  47. Yao Q, Glorioso JC, Evans CH, et al.: Adenoviral mediated delivery of FAS ligand to arthritic joint causes extensive apoptosis in the synovial lining. J Gene Med 2000, 2:210–219.

    Article  PubMed  CAS  Google Scholar 

  48. Zhang H, Yang Y, Horton JL, et al.: Amelioration of collageninduced arthritis by CD95 (Apo-1/Fas)-ligand gene transfer. J Clin Invest 1997, 100:1951–1957.

    PubMed  CAS  Google Scholar 

  49. Goossens PH, Schouten GJ, ’t Hart BA, et al.: Feasibility of adenovirus-mediated nonsurgical synovectomy in collagen-induced arthritis-affected rhesus monkeys. Hum Gene Ther 1999, 10:1139–1149.

    Article  PubMed  CAS  Google Scholar 

  50. Sant SM, Suarez TM, Moalli MR, et al.: Molecular lysis of synovial lining cells by in vivo herpes simplex virus-thymidine kinase gene transfer. Hum Gene Ther 1998, 9:2735–2743.

    PubMed  CAS  Google Scholar 

  51. Taniguchi K, Kohsaka H, Inoue N, et al.: Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis. Nat Med 1999, 5:760–767. jThis paper reports a novel, gene-based approach to reduce synovial mass in rheumatoid arthritis.

    Article  PubMed  CAS  Google Scholar 

  52. Wahlen JD, Thomson AW, Lu L, et al.: Transfer and expression of the viral IL-10 gene in vivo induces a suppressor population of antigen presenting cells which adoptively transfer suppression to soluble antigens. Submitted TO WHAT? This work explains the beneficial contralateral effect induced by local gene therapy. Macrophages and dendritic cells transduced with vIL-10 can, by adoptive transfer, inhibit DTH reactions when pulsed with the relevant inciting antigen.

  53. Decaris E, Guingamp C, Chat M, et al.: Evidence for neurogenic transmission inducing degenerative cartilage damage distant from local inflammation. Arthritis Rheum 1999, 42:1951–1960.

    Article  PubMed  CAS  Google Scholar 

  54. Hickey WF: Leukocyte traffic in the central nervous system: the participants and their roles. Semin Immunol 1999, 11:125–137.

    Article  PubMed  CAS  Google Scholar 

  55. Evans CH, Ghivizzani SC, Herndon JH, et al.: Clinical trials in the gene therapy of arthritis. Clin Orthop 379(Suppl):S300–307.

  56. Mageed RA, Adams G, Woodrow D, et al.: Prevention of collagen-induced arthritis by gene delivery of soluble p75 tumour necrosis factor receptor. Gene Ther 1998, 5:1584–1592.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Center for Molecular Orthopaedics, Harvard Medical School, 221 Longwood Avenue, BL-152, 02115, Boston, MA, USA

    Christopher H. Evans PhD

Authors
  1. Elvire Gouze PhD
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  2. Steven C. Ghivizzani PhD
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  3. Paul D. Robbins PhD
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  4. Christopher H. Evans PhD
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Gouze, E., Ghivizzani, S.C., Robbins, P.D. et al. Gene therapy for rheumatoid arthritis. Curr Rheumatol Rep 3, 79–85 (2001). https://doi.org/10.1007/s11926-001-0054-x

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  • DOI: https://doi.org/10.1007/s11926-001-0054-x

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