Abstract
Osteoarthritis (OA) is a major health problem in urgent need of better treatment. Gene therapy offers to meet this need. Of the different strategies for using gene therapy in OA, local gene transfer to synovium is in the most advanced stage of development. Local gene transfer brings several advantages, including a focused, local therapy that promises greater efficacy with reduced side-effects, potentially at far lower cost. Moreover, its clinical feasibility has already been confirmed in two Phase I studies of gene therapy for rheumatoid arthritis. Although there are numerous candidate genes of potential use in treating OA genetically, considerable evidence identifies interleukin-1 (IL-1) as a key target. The existence of a natural antagonist, the IL-1 receptor antagonist (IL-1Ra), provides a means with which to inhibit its biologic actions. Clinical studies are suggested in which IL-1Ra complementary DNA is transferred to knee joints shortly before they are surgically replaced with prostheses. This will permit the ready assessment of the safety and efficiency of gene transfer and expression in the human OA knee, as well as permitting preliminary functional data to be obtained, as a prelude to phase II efficacy studies. At this point, the major barriers to progress are financial rather than intellectual or technical.
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References and Recommended Reading
Evans CH, Robbins PD: Potential treatment of osteoarthritis by gene therapy. Rheum Dis Clin North Am 1999, 25:333–344.
Thomas CE, Ehrhardt A, Kay MA: Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet 2003, 4:346–358.
Miagkov AV, Varley AW, Munford RS, Makarov SS: Endogenous regulation of a therapeutic transgene restores homeostasis in arthritic joints. J Clin Invest 2002, 109:1223–1229.
Davis ME: Non-viral gene delivery systems. Curr Opin Biotechnol 2002, 13:128–131.
Gene therapy clinical trials database. Web site of the Journal of Gene Medicine. Available at http://www.wiley.co.uk/genetherapy/ clinical. Accessed August 5, 2003.
Evans CH, Ghivizzani SC, Herndon JH, et al.: Clinical trials in the gene therapy of arthritis. Clin Orthop 2000, 379(suppl):S300-S307.
Bandara G, Robbins PD, Georgescu HI, et al.: Gene transfer to synoviocytes: prospects for gene treatment of arthritis. DNA Cell Biol 1992, 11:227–231.
Bandara G, Mueller GM, Galea-Lauri J, et al.: Intra-articular expression of biologically active interleukin 1-receptorantagonist protein by ex vivo gene transfer. Proc Natl Acad Sci U S A 1993, 90:10764–10768.
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.
Ghivizzani SC, Oligino TJ, Glorioso JC, et al.: Direct gene delivery strategies for the treatment of rheumatoid arthritis. Drug Discov Today 2001, 6:259–267.
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.
Watanabe S, Imagawa T, Boivin GP, et al.: Adeno-associated virus mediates long-term gene transfer and delivery of chondroprotective IL-4 to murine synovium. Mol Ther 2000, 2:147–152.
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.
Zhang HG, Xie J, Yang P, et al.: Adeno-associated virus production of soluble tumor necrosis factor receptor neutralizes tumor necrosis factor alpha and reduces arthritis. Hum Gene Ther 2000, 11:2431–2442.
Chan JM, Villarreal G, Jin WW, et al.: Intra-articular gene transfer of TNFR:Fc suppresses experimental arthritis with reduced systemic distribution of the gene product. Mol Ther 2002, 6:727–736.
Gouze E, Pawliuk R, Gouze JN, et al.: Lentiviral-mediated gene delivery to synovium: potent intra-articular expression with amplification by inflammation. Mol Ther 2003, 7:460–466. The data reported here (and in [17]) demonstrate the remarkable ability of lentiviruses to transduce synovium in vivo.
Gouze E, Pawliuk R, Pilapil C, et al.: In vivo gene delivery to synovium by lentiviral vectors. Mol Ther 2002, 5:397–404. The data reported here (and in [16]) demonstrate the remarkable ability of lentiviruses to transduce synovium in vivo.
Otani K, Nita I, Macaulay W: Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy. J Immunol 1996, 156:3558–3562.
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.
Arend WP, Evans CH: Interleukin-1 receptor antagonist. In The Cytokine Handbook. Edited by Thomson AW, Lotze MT. London: Academic Press; 2003:669–708.
Mi Z, Ghivizzani SC, Lechman ER, et al.: Adenovirus-mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan synthesis in rabbit joints. Arthritis Rheum 2000, 43:2563–2570.
Nixon A: Gene mediated restoration of cartilage by combination insulin-like growth factor-1/interleukin-1 receptor antagnoist therapy. Gene Ther 2003, in press.
Mi Z, Ghivizzani SC, Lechman E, et al.: Adverse effects of adenovirus-mediated gene transfer of human transforming growth factor beta 1 into rabbit knees. Arthritis Res Ther 2003, 5:R132-R139.
Bakker AC, van de Loo FA, van Beuningen HM, et al.: Overexpression of active TGF-beta-1 in the murine knee joint: evidence for synovial-layer-dependent chondro-osteophyte formation. Osteoarthritis Cartilage 2001, 9:128–136.
Gelse K, von der Mark K, Aigner T, et al.: Articular cartilage repair by gene therapy using growth factor-producing mesenchymal cells. Arthritis Rheum 2003, 48:430–441.
Gouze JN: Adenovirus-mediated gene transfer of glutamine: fructose-6-phosphate amidotransferase antagonizes the effects if interleukin-1 beta on rat chondrocytes. Osteoarthritis Cartilage 2003, in press.
Shuler FD, Georgescu HI, Niyibizi C, et al.: Increased matrix synthesis following adenoviral transfer of a transforming growth factor beta1 gene into articular chondrocytes. J Orthop Res 2000, 18:585–592.
Smith P, Shuler FD, Georgescu HI, et al.: Genetic enhancement of matrix synthesis by articular chondrocytes: comparison of different growth factor genes in the presence and absence of interleukin-1. Arthritis Rheum 2000, 43:1156–1164.
Tomita T: In vivo direct gene transfer into articular cartilage by intra-articular injection mediated by HVJ (Sendai virus) and liposomes. Arthritis Rheum 1997, 40:901–906.
Grossin L, Cournil-Henrionnet C, Mir LM, et al.: Direct gene transfer into rat articular cartilage by in vivo electroporation. Faseb J 2003, 17:829–835.
Arai Y, Kubo T, Fushiki S, et al.: Gene delivery to human chondrocytes by an adeno associated virus vector. J Rheumatol 2000, 27:979–982.
Nishida K: Adenovirus-mediated gene transfer to nucleus pulposus cells: implications for the treatment of intervertebral disc degeneration. Spine 1998, 23:2437–2442.
Kang R, Marui T, Ghivizzani SC, et al.: Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: a feasibility study. Osteoarthritis Cartilage 1997, 5:139–143.
Baragi VM, Renkiewicz RR, Qiu L, et al.: Transplantation of adenovirally transduced allogeneic chondrocytes into articular cartilage defects in vivo. Osteoarthritis Cartilage 1997, 5:275–282.
Mason JM, Grande DA, Barcia M, et al.: Expression of human bone morphogenic protein 7 in primary rabbit periosteal cells: potential utility in gene therapy for osteochondral repair. Gene Ther 1998, 5:1098–1104.
Hidaka C, Goodrich LR, Chen CT, et al.: Acceleration of cartilage repair by genetically modified chondrocytes over expressing bone morphogenetic protein-7. J Orthop Res 2003, 21:573–583.
Evans CH, Ghivizzani SC, Smith P, et al.: Using gene therapy to protect and restore cartilage. Clin Orthop 2000, 379(suppl):S214-S219.
Gelse K, von der Mark K, Schneider H: Cartilage regeneration by gene therapy. Curr Gene Ther 2003, 3:305–317.
Palmer G, Pascher A, Gouze E, et al.: Development of genebased therapies for cartilage repair. Crit Rev Eukaryot Gene Expr 2002, 12:259–273.
Dingle JT:The role of cellular interactions in joint erosions. Clin Orthop 1984, 182:24–30.
Pelletier JP, Faure MP, DiBattista JA, et al.: Coordinate synthesis of stromelysin, interleukin-1, and oncogene proteins in experimental osteoarthritis: an immunohistochemical study. Am J Pathol 1993, 142:95–105.
Caron JP, Fernandes JC, Martel-Pelletier J, et al.: Chondroprotective effect of intra-articular injections of interleukin-1 receptor antagonist in experimental osteoarthritis: suppression of collagenase-1 expression. Arthritis Rheum 1996, 39:1535–1544.
Towle CA, Hung HH, Bonassar LJ, et al.: Detection of interleukin-1 in the cartilage of patients with osteoarthritis: a possible autocrine/paracrine role in pathogenesis. Osteoarthritis Cartilage 1997, 5:293–300.
Melchiorri C, Meliconi R, Frizziero L, et al.: Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis. Arthritis Rheum 1998, 41:2165–2174.
Attur MG, Dave MN, Leung MY, et al.: Functional genomic analysis of type II IL-1beta decoy receptor: potential for gene therapy in human arthritis and inflammation. J Immunol 2002, 168:2001–2010. This (as well as [46•]) is a report on data obtained with human biopsy material obtained at the time of total knee joint replacement for OA. They provide strong evidence for a unique and central role for IL-1 in the pathophysiologic changes that occur in OA cartilage.
Attur MG, Dave M, Cipolletta C, et al.: Reversal of autocrine and paracrine effects of interleukin 1 (IL-1) in human arthritis by type II IL-1 decoy receptor: potential for pharmacological intervention. J Biol Chem 2000, 275:40307–40315. This (as well as [45•]) is a report on data obtained with human biopsy material obtained at the time of total knee joint replacement for OA. They provide strong evidence for a unique and central role for IL-1 in the pathophysiologic changes that occur in OA cartilage.
Martel-Pelletier J, McCollum R, DiBattista J, et al.: The interleukin-1 receptor in normal and osteoarthritic human articular chondrocytes: identification as the type I receptor and analysis of binding kinetics and biologic function. Arthritis Rheum 1992, 35:530–540.
Eger W, Schumacher BL, Mollenhauer J, et al.: Human knee and ankle cartilage explants: catabolic differences. J Orthop Res 2002, 20:526–534.
Pelletier JP, Caron JP, Evans C, et al.: In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum 1997, 40:1012–1019.
Fernandes J, Tardif G, Martel-Pelletier J, et al.: In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints: prevention of osteoarthritis progression. Am J Pathol 1999, 154:1159–1169.
Frisbie DD, Ghivizzani SC, Robbins PD, et al.: Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther 2002, 9:12–20. This study provides strong evidence of the value of IL-1Ra gene transfer in an experimental model of OA. Gene transfer occurred 14 days after initiation of the model and was thus tested in a therapeutic mode. The ability of gene therapy to reduce the lameness of the animals indicates improvement in function, as well as in laboratory values.
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Evans, C.H. Gene therapies for osteoarthritis. Curr Rheumatol Rep 6, 31–40 (2004). https://doi.org/10.1007/s11926-004-0081-5
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DOI: https://doi.org/10.1007/s11926-004-0081-5