Suppression of early experimental osteoarthritis by gene transfer of interleukin‐1 receptor antagonist and interleukin‐10

Abstract

Gene therapy olTers a radically different approach to the treatment of arthritis. We demonstrated that cDNA coding for human interleukin-1 receptor-antagonist protein (IL-1Ra) and cDNA coding for human interleukin-I0 (IL-10) can be delivered. by ex vivo techniques, to the synovial lining of joints, intra-articular expression of gene significantly reduced cartilage matrix degradation and cartilage breakdown. To achieve this, lapine synoviocytes were first transduced in culture by retroviral infection. The genetically modified synoviocytes were then transplanted by intra-articular injection into the knee joints of OA rabbits, assay of joint lavages confirmed that the gene expression was not lost 14 days after transfer. Knees receiving the IL-IRa gene had significantly reduced cartilage breakdown. Delivery of the IL-I0 gene was less effective, having only a moderate effect on cartilage breakdown. When both genes were injected together, there was a greater inhibition of cartilage breakdown, suggesting that simultaneous gene delivery may be necessary to treat OA by targeting the activities of multiple inflammatory effectors.

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

“…Combined delivery with other factors, such as those that prevent cartilage degradation (IL1Ra, sTNFR, IL-10) (12)(13)(14)21) or correct the OA phenotype in the cells (SOX9) (20,26,27), might be useful to further attenuate pathological events in OA. Again, rAAVs are strong tools, since they can be used for cotransduction strategies in OA chondrocytes and cartilage (20).…”

“…Current approaches that aim at re-equilibrating the metabolic balance in OA cartilage are on the basis of the transfer of sequences coding for agents that either counteract the processes of matrix degradation or enhance the synthesis of matrix components. Protective effects against cartilage breakdown have been documented in experimental models of OA using sequences coding for inhibitors of inflammatory pathways (an IL-1 receptor antagonist [IL-1Ra], soluble TNF receptor [sTNFR], tissue inhibitor of metalloproteinases [TIMP-1]) (6)(7)(8)(9)(10)(11)(12)(13)(14) or factors such as IL-10 (12), heat shock protein 70 (15), glutamine:fructose-6-phosphate amidotransferase (16), thrombospontin-1 (17), kallistatin (18) and inhibitors of nuclear factor κB (19). Even though application of these stimuli was capable of containing cartilage degradation, it was not sufficient to compensate for the loss of matrix elements and cells and to reestablish an original cartilage surface.…”

“…In contrast with vectors derived from adenoviruses (6,10,13,14,(16)(17)(18)(19)21,22,25) and retroviruses (7,11,12,23,26,30) or with nonviral compounds (8,15,28,29), systems based on the replication-defective, nonpathogenic human adeno-associated virus (AAV) may provide better tools for OA, since recombinant AAV (rAAV) can deliver genes in nondividing cells such as chondrocytes both in vitro and in situ in their dense extracellular matrix at high efficiencies and for extended periods of time (20,24,27,31). Also, removal of the viral protein coding sequences in rAAV make them less immunogenic than adenoviral vectors characterized by shortterm transgene expression levels (32).…”

Expression of IL-1β Receptor Antagonist in Patients with Severe Osteoarthritis of the Knee–The Mechanism Limiting the Inflammation in Osteoarthritis

“…Animals with experimentally induced OA showed a significant clinical and histological improvement after intraarticular administration of IL-1Ra [29,30]. Improvement in almost all determinants of the disease and reduction joint pain have been described in clinical studies conducted on patients treated with IL-1Ra [9].…”

Immune Modulation to Improve Tissue Engineering Outcomes for Cartilage Repair in the Osteoarthritic Joint

“…133 The effects of retrovirally delivered human IL-1RA and IL-10 have also been assessed following injection in to the knee joint in a rabbit model of OA. 134 Intra-articular expression of these genes was found to have a chondroprotective effect with an evident reduction in cartilage degradation. Administration of both IL-1RA and IL-10 was reported to have a greater effect, compared with administration of either gene alone.…”