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Gene therapy for rheumatoid arthritis starts clinical trials
THE LANCET
SCIENCE AND MEDICINE
NEWS Gene therapy for rheumatoid arthritis starts clinical trials
R
esearchers at the University of Pittsburgh Medical Center in the USA have begun testing a genetic therapy for rheumatoid arthritis in human beings. The therapy involves injecting rheumatic joints with genetically altered synovial cells that express an antagonist to interleukin-1 (IL-1). Although the cause of rheumatoid arthritis is not clear, it is known that in this disease IL-1 is produced by a number of different cells within affected joints, including activated macrophages, synovial fibroblasts, and endothelial cells. In addition to its pro-inflammatory effects, IL-1 stimulates the formation of the invasive rheumatoid pannus and promotes the enzymatic destruction of cartilage and bone. “It comes from everywhere and it does everything”, says British molecular biologist Chris Evans, one of the study’s two principal investigators. The antagonist being used in this trial, called IL-1 receptor antagonist (IL-1Ra), is a naturally occurring
protein that was first cloned from macrophages by William Arrend of the University of Colorado Health Sciences Center (Denver, USA). Evans and his colleague Paul Robbins, the trial’s other lead investigator, have previously shown in a rabbit model of rheumatoid arthritis that it is possible to significantly reduce inflammation by introducing modified synovial cells capable of expressing IL-1Ra into affected joints. Nine women will participate in the human trial that began last month. All will be postmenopausal to eliminate the possibility that the altered gene might enter the germline and be passed to subsequent generations. The first volunteer to undergo the experiment is Carlene Lauffer, a 68year-old food-services manager whose knuckles have been destroyed by rheumatoid arthritis and are to be replaced with artificial joints. Last April, during an operation to fuse her thumb, synovial cells were removed from Lauffer’s thumb joint and cul-
Cytokines and rheumatoid arthritis Rheumatoid arthritis is one of a number of organ-specific autoimmune diseases thought to be due to inflammatory (delayed-type hypersensitivity, DTH) immune responses. DTH responses are cellular immune responses dependent on CD4 Thelper cells and macrophages. Both of these cell types are present in the inflammed synovium in rheumatoid arthritis. The macrophages function both as the cell types causing tissue damage and, when activated, as cells capable of presenting antigen to recruit more T-cells, thereby amplifying the deleterious immune response. Communication between macrophages and T-cells and the induction of inflammation are dependent on cytokines secreted by the two cell types. The most important of these cytokines in inflammation are interleukin-1 and TNF-alpha. A number of therapies targeting these inflammatory cytokines and the CD4 Thelper cells are being developed for clinical use. As well as the IL-1 antagonist approach described above, therapies in clinical trial include the following: Soluble TNF receptors are being used to block the action of TNF-alpha. Anti-CD4 antibodies are being used to try and reprogramme the T-helper cells involved in the disease process. In an alternative approach that attempts to switch off the T-cell response during the inflammatory process, potential target antigen (bovine collagen) is being administered orally. Preliminary results have been reported for the anti-CD4 trials but not for the other approaches.
Vol 348 • August 3, 1996
tured. The cells were then divided into two batches, one of which was exposed to a replication-defective mouse retroviral vector containing the gene for the antagonist, IL-1Ra. The other batch was not exposed to the vector. In the experiment, four of Lauffer’s knuckles were first injected
in a blinded fashion. Two joints received injections containing the genetically altered cells and two received the unaltered cells. One week later all four knuckles were removed as part of the surgery to replace them. “We are now in the process of analysing the joint tissue and fluids to see if we got gene transfer, gene expression, a gene product that was biologically active, and whether the joint responded to it”, Evans said. Because Lauffer’s disease was so advanced, the researchers did not expect to see clinical improvement. But, Evans said, it will be possible to see if inhibition of IL-1 effectively reduces the expression of other cytokines, such as IL-6 and IL-8, as well as certain prostaglandins. Although the preliminary results of this first experiment may be available before the end of the year, the entire trial is expected to take at least 2 years, say the researchers. Michael McCarthy
323
SCIENCE AND MEDICINE
NEWS Gene therapy for rheumatoid arthritis starts clinical trials
R
esearchers at the University of Pittsburgh Medical Center in the USA have begun testing a genetic therapy for rheumatoid arthritis in human beings. The therapy involves injecting rheumatic joints with genetically altered synovial cells that express an antagonist to interleukin-1 (IL-1). Although the cause of rheumatoid arthritis is not clear, it is known that in this disease IL-1 is produced by a number of different cells within affected joints, including activated macrophages, synovial fibroblasts, and endothelial cells. In addition to its pro-inflammatory effects, IL-1 stimulates the formation of the invasive rheumatoid pannus and promotes the enzymatic destruction of cartilage and bone. “It comes from everywhere and it does everything”, says British molecular biologist Chris Evans, one of the study’s two principal investigators. The antagonist being used in this trial, called IL-1 receptor antagonist (IL-1Ra), is a naturally occurring
protein that was first cloned from macrophages by William Arrend of the University of Colorado Health Sciences Center (Denver, USA). Evans and his colleague Paul Robbins, the trial’s other lead investigator, have previously shown in a rabbit model of rheumatoid arthritis that it is possible to significantly reduce inflammation by introducing modified synovial cells capable of expressing IL-1Ra into affected joints. Nine women will participate in the human trial that began last month. All will be postmenopausal to eliminate the possibility that the altered gene might enter the germline and be passed to subsequent generations. The first volunteer to undergo the experiment is Carlene Lauffer, a 68year-old food-services manager whose knuckles have been destroyed by rheumatoid arthritis and are to be replaced with artificial joints. Last April, during an operation to fuse her thumb, synovial cells were removed from Lauffer’s thumb joint and cul-
Cytokines and rheumatoid arthritis Rheumatoid arthritis is one of a number of organ-specific autoimmune diseases thought to be due to inflammatory (delayed-type hypersensitivity, DTH) immune responses. DTH responses are cellular immune responses dependent on CD4 Thelper cells and macrophages. Both of these cell types are present in the inflammed synovium in rheumatoid arthritis. The macrophages function both as the cell types causing tissue damage and, when activated, as cells capable of presenting antigen to recruit more T-cells, thereby amplifying the deleterious immune response. Communication between macrophages and T-cells and the induction of inflammation are dependent on cytokines secreted by the two cell types. The most important of these cytokines in inflammation are interleukin-1 and TNF-alpha. A number of therapies targeting these inflammatory cytokines and the CD4 Thelper cells are being developed for clinical use. As well as the IL-1 antagonist approach described above, therapies in clinical trial include the following: Soluble TNF receptors are being used to block the action of TNF-alpha. Anti-CD4 antibodies are being used to try and reprogramme the T-helper cells involved in the disease process. In an alternative approach that attempts to switch off the T-cell response during the inflammatory process, potential target antigen (bovine collagen) is being administered orally. Preliminary results have been reported for the anti-CD4 trials but not for the other approaches.
Vol 348 • August 3, 1996
tured. The cells were then divided into two batches, one of which was exposed to a replication-defective mouse retroviral vector containing the gene for the antagonist, IL-1Ra. The other batch was not exposed to the vector. In the experiment, four of Lauffer’s knuckles were first injected
in a blinded fashion. Two joints received injections containing the genetically altered cells and two received the unaltered cells. One week later all four knuckles were removed as part of the surgery to replace them. “We are now in the process of analysing the joint tissue and fluids to see if we got gene transfer, gene expression, a gene product that was biologically active, and whether the joint responded to it”, Evans said. Because Lauffer’s disease was so advanced, the researchers did not expect to see clinical improvement. But, Evans said, it will be possible to see if inhibition of IL-1 effectively reduces the expression of other cytokines, such as IL-6 and IL-8, as well as certain prostaglandins. Although the preliminary results of this first experiment may be available before the end of the year, the entire trial is expected to take at least 2 years, say the researchers. Michael McCarthy
323