Gene Transfer to Synovial Cells by Intra-Articular Administration of Plasmid DNA

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Abstract
We studied reporter gene expression in synovial tissue after intra-articular administration of an expression plasmid into the knees of rabbits and rats. In both species, administration of a plasmid encoding (β-galactosidase led to gene expression in the synovial cells lining the joint. Expression correlated with the presence of plasmid DNA in synovial tissue extracts. Studies with a plasmid encoding chloramphenicol acetyltransferase demonstrated that gene expression persists for 2–5 days after administration. Southern blotting demonstrated that the administered plasmid was taken up rapidly by synovial tissue and degraded. By 24 hr after administration, no intact plasmid could be detected by Southern blotting, although small amounts of plasmid could be amplified by PCR up to 7 days. Administration of a plasmid encoding human growth hormone demonstrated that this product could be expressed from synovial cells and secreted into the synovial fluid. The histological distribution of gene expression in synovium resembles the known distribution of particulate materials injected into the joint and suggests that plasmid DNA is taken up by nonspecific endocytosis like other particulate materials during the remodeling of synovial fluid. The mechanism by which certain cells within the body are able to take up purified DNA and express products from plasmid expression vectors remains unknown. We report uptake and expression of reporter genes in synovial cells after injection of plasmid into the synovial fluid of the joint. The distribution of gene expression resembles the distribution of particles administered into the joint, suggesting that plasmid DNA is taken up by passive endocytosis during the normal remodeling of synovial fluid. The ability to deliver genes to synovial cells introduces the possibility of treating arthritis using nonviral gene delivery systems.