Molecular Lysis of Synovial Lining Cells by In Vivo Herpes Simplex Virus-Thymidine Kinase Gene Transfer

Abstract

Herpes simples virus thymidine kinase (HSV-TK) expression plasmid DNA was injected into the joint space of rabbits with antigen-induced arthritis (AIA). Purified plasmid DNA was able to mediate transfection of synovial lining cells and transient overexpression of HSV-TK in the context of active synovial inflammation. The pharmacodynamic distribution of intraarticular expression plasmid DNA was confined to the joint space. Arthritic rabbits treated with intraarticular expression plasmid DNA followed by intravenous ganciclovir (GCV, 5 mg/kg) twice daily for 3 days showed histologic evidence of synovial lining layer cytolysis when articular tissues were examined 21 days posttreatment. There was also a reduction in joint swelling in the TK-treated knees. No untoward clinical effects were observed in the rabbits and no evidence of cytolytic damage specific to the TK-GCV gene therapy was observed either in the articular cartilage or bone. The application of TK-GCV intraarticular gene therapy using purified expression plasmid DNA for the induction of synovial cytolysis may be applicable to the treatment of human inflammatory arthritis.

Overview summary

Previous studies have shown that synovial lining cells are susceptible to in vivo transfection using purified expression plasmid DNA. Roessler et al. now report on the use of a plasmid that mediates transient overexpression of herpes simplex virus thymidine kinase to transfect synovial lining cells in an animal model of proliferative inflammatory arthritis. After in vivo intraarticular transfection using the pNGVL-TK expression plasmid, the animals were treated with intravenous ganciclovir for a period of 3 days. They report that examination of the synovial tissues 21 days after completion of the gene therapy showed evidence of cytolysis that was confined to the synovial lining cells within inflamed synovium. No evidence of cytolysis or necrosis was observed in articular cartilage present within the treated joints. Similar methods to achieve a molecular lysis of the synovial lining layer may have applicability to the treatment of human inflammatory arthritis.