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From the Osteoarthritis Research Unit,*
Centre
Hospitalier de l'Université de Montréal, Campus
Notre-Dame, Montréal, Québec, Canada, and the Animal
Health Biological Discovery
Central
Research Division, Groton, Connecticut
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,
AP-DLRIE/DOPE, and a DNA plasmid, VR1012.
Group 3 received three consecutive injections of saline containing 1000
µg 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 µg) 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.
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