Gene therapy of the rheumatic diseases: 1998 to 2008

Abstract

During the decade since the launch of Arthritis Research, the application of gene therapy to the rheumatic diseases has experienced the same vicissitudes as the field of gene therapy as a whole. There have been conceptual and technological advances and an increase in the number of clinical trials. However, funding has been unreliable and a small number of high-profile deaths in human trials, including one in an arthritis gene therapy trial, have provided ammunition to skeptics. Nevertheless, steady progress has been made in a number of applications, including rheumatoid arthritis and osteoarthritis, Sjögren syndrome, and lupus. Clinical trials in rheumatoid arthritis have progressed to phase II and have provided the first glimpses of possible efficacy. Two phase I protocols for osteoarthritis are under way. Proof of principle has been demonstrated in animal models of Sjögren syndrome and lupus. For certain indications, the major technological barriers to the development of genetic therapies seem to have been largely overcome. The translational research necessary to turn these advances into effective genetic medicines requires sustained funding and continuity of effort.

Figure 1

English language publications on arthritis gene therapy in the refereed literature. The data are based on a PubMed search using 'arthritis gene therapy' as the search term. The first paper on arthritis gene therapy was published in 1992 [27]. The first efficacy data for animal models of rheumatoid arthritis (RA) appeared in 1996 [103,104], and the first efficacy data for animal models of osteoarthritis (OA) followed a year later [79]. The first human trial for RA began in 1996 [29]. Seven clinical trials for RA and OA have been initiated, one of them reaching phase II (Table 1). The first evidence of possible clinical responses to gene transfer was published this year [31]. Reprinted with permission [105].

Figure 2

Strategies for the gene therapy of arthritis. Reprinted in a modified form with permission [28,106].

Figure 3

Fibroblasts resident in fibrous articular tissues support stable expression of exogenous transgenes. Following intra-articular injection of lentivirus-GFP or Ad.GFP into the knees of nude rats, groups of animals were sacrificed at days 5 and 168. The knee joints and surrounding tissues were harvested intact, decalcified, and processed for histology. For each joint, the approximate positions of fluorescent cells identified in serial, sagittal whole-knee sections were tabulated in green on knee joint diagrams similar to those shown on the left. The diagrams shown are representative of the results observed with both viruses at the respective times. On the right, images characteristic of the appearance of the GFP⁺ cells in tissue sections at the different times are shown (×20 magnification). Lines indicate the approximate regions represented by the tissue sections. The numbers of GFP⁺ cells in the synovium and subsynovium were reduced dramatically at day 168. The density and distribution of GFP⁺ cells in the tendon, ligament, and fibrous synovium were largely unchanged over the duration of the experiment. No fluorescent cells were seen in the articular cartilage with either virus at any time point. B, bone; GFP, green fluorescent protein; M, muscle; P, patella. Reprinted with permission [48].

Figure 4

A model based upon trafficking of antigen-presenting cells (APCs) to explain the contralateral effect. Introduction of a suitable vector, in this example one encoding viral interleukin-10 (vIL-10), into an inflamed joint transduces synovium and APCs. Lymphocytes are very difficult to transduce, as reflected in the figure. Intra-articular antigen presentation thus occurs in the presence of a high local concentration of vIL-10 produced by the synovium, the APC, or both. Under these conditions, the immune response deviates toward a therapeutic Th2 response. Lymphocytes and APCs then traffic to other joints via the blood stream or lymphatics, where they suppress disease. Reprinted with permission [28].