The goal of this study was to determine the efficacy of local
IL-1Ra gene therapy by intra-articular plasmid
injections on structural changes in the
meniscectomy rabbit model of
osteoarthritis. A partial
meniscectomy of the right knee was performed on the rabbits through a medial parapatellar incision. The rabbits were then divided into four experimental groups. Group 1 received no treatment. Group 2 received three consecutive
intra-articular injections at 24-hour intervals of
0.9% saline containing a
lipid, gammaAP-
DLRIE/DOPE, and
a DNA plasmid, VR1012. Group 3 received three consecutive
injections of saline containing 1000 microg of canine
IL-1Ra plasmid and
lipid. The
injections were given starting 4 weeks post-surgery. Rabbits from Group 1 were killed 4 weeks post-surgery, and all other rabbits 8 weeks post-surgery. The severity of macroscopic and microscopic changes on cartilage on the medial and femoral condyles and tibial plateaus and synovium were graded separately. Specimens were also processed for immunohistochemical staining using a rabbit polyclonal antibody against canine
IL-1Ra. The level of canine
IL-1Ra in synovial fluid was determined using
enzyme-linked
immunosorbent assay. The presence of the
DNA plasmid in the synovium was tested by polymerase chain reaction. A significant reduction in the width of
osteophytes and size of macroscopic lesions (P < 0.04) was observed, and was dependent on the amount of
IL-1Ra plasmid injected. A significant reduction was also noted in the severity of histologic cartilage lesions (P < 0.01) in the group that received the highest dosage (1000 microg) 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-1Ra plasmid. Polymerase chain reaction 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 demonstrates that direct in vivo transfer of the
IL-1Ra gene into
osteoarthritis knee cells using
intra-articular injections of a plasmid vector and
lipids can significantly reduce the progression of experimental
osteoarthritis. This avenue may therefore represent a promising future treatment for
osteoarthritis.