Permission was received from NIH and the FDA to undertake a phaseI clinical study to determine the safety and feasibility of the retroviral, ex vivo transfer of a human IL-1Ra cDNA to human rheumatoid joints. Eligible patients were post-menopausal females with end-stage RA requiring replacement of the metacarpophalangeal (MCP) joints of one hand and also requiring surgery on at least one other joint. The latter surgery provided the opportunity to recover autologous synovial tissue from which to establish synovial cell cultures. Half of each patients' cells were transduced with the retrovirus MFG-IRAP, while the other half remained as untransduced controls. After safety testing of both sets of cells, the autologous synoviocytes were injected into the subjects' MCP joints; in a double-blinded manner, two joints received the genetically modified cells, and two joints received control cells. One week later, all four MCP joints were surgically removed during joint replacement surgery and the retrieved joint tissues analyzed for transgene expression. Nine patients were treated in a dose-escalation manner, receiving from 106–107 cells per MCP joint.
All patients tolerated the procedure well, and no adverse events related to the study were reported. Transcripts originating from the transgene were detected by RT-PCR in all joints that received genetically modified cells, but in only one of the control joints. Analysis of certain samples by in situ hybridization and immunohistochemistry confirmed that cells expressing the transgene were located in clumps on the synovial surface. Synovial cells were recovered from the retrieved tissues and placed into cell culture. Concentrations of IL-1Ra were higher in media conditioned by cells recovered from genetically modified joints than in media conditioned by cells from control joints. Although the design of the study precluded assessment of clinical efficacy, several patients reported symptomatic improvement; this was attributed to a placebo effect.
These data confirm that it is possible to transfer genes to human, arthritic joints and to express those genes intra-articularly in a manner that is safe and acceptable to patients. This encourages further development of gene therapies for the treatment of arthritis in humans.
Supported by grant number RO1 AR43623 from NIAMS.