In vivo transfer of interleukin-1 receptor antagonist gene in osteoarthritic rabbit knee joints - Prevention of osteoarthritis progression

The goal of this study was to determine the efficacy of local IL-1Ra gene t herapy by intra-articular plasmid injections on structural changes in the m eniscectomy rabbit model of osteoarthritis. A partial meniscectomy of the r ight knee was performed on the rabbits through a medial parapatellar incisi on. The rabbits were then divided into four experimental groups. Group 1 re ceived no treatment. Group 2 received three consecutive intra-articular inj ections at 24-hour intervals of 0.9% saline containing a lipid, gamma AP-DL -RIE/DOPE, and a DNA plasmid, VR1012. Group 3 received three consecutive in jections of saline containing 1000 mu g of canine IL-1Ra plasmid and lipid. The injections were given starting 4 weeks post-surgery. Rabbits from Grou p 1 were killed 4 weeks post-surgery, and all other rabbits 8 weeks post-su rgery, The severity of macroscopic and microscopic changes on cartilage on the medial and femoral condyles and tibial plateaus and synovium were grade d separately. Specimens were also processed for immunohistochemical stainin g using a rabbit polyclonal antibody against canine IL-1Ra. The level of ca nine IL-1Ra in synovial fluid was determined using enzyme-linked immunosorb ent assay. The presence of the DNA plasmid in the synovium was tested by po lymerase chain reaction. A significant reduction in the width of osteophyte s and size of macroscopic lesions (P < 0.04) was observed, and was dependen t on the amount of IL-IRa plasmid injected. A significant reduction was als o noted in the severity of histologic cartilage lesions CP < 0.01) in the g roup that received the highest dosage (1000 Erg) of IL-1Ra plasmid, IL-1Ra was detected in synovial fluid by enzyme-linked immunosorbent assay and by immunohistochemical staining in the synovium and cartilage of rabbits that received injections containing the IL-IRa plasmid. Polymerase chain reactio n analysis of synovial DNA revealed the presence of the cloned cDNA dog IL- 1Ra up to 4 weeks after the first intra-articular injection. This study dem onstrates that direct in vivo transfer of the IL-1Ra gene into osteoarthrit is knee cells using intra-articular injections of a plasmid vector and lipi ds can significantly reduce the progression of experimental osteoarthritis. This avenue may therefore represent a promising future treatment for osteo arthritis.