Feasibility of Adenovirus-Mediated Nonsurgical Synovectomy in Collagen-Induced Arthritis-Affected Rhesus Monkeys

Abstract

Gene transfer to synovial tissue by adenoviral vectors (Ad) was studied in vitro in cultured human synoviocytes and in vivo in seven primates with arthritis. Hyperplastic synovium was efficiently transduced with Ad.lacZ in vitro and in vivo in rhesus monkeys with collagen-induced arthritis, whereas chondrocytes were not transduced. Intraarticular injection of recombinant Ad harboring the luciferase gene showed the presence of reporter gene products only in Ad-injected joints. In addition, the feasibility of synovectomy by Ad harboring the herpes simplex virus thymidine kinase gene (tk) was studied. In vitro infection of synovium from rheumatoid arthritis patients with Ad.TK, followed by administration of ganciclovir, resulted in death of >90% of the synoviocytes. By mixing Ad.TK-infected with noninfected cells, it appeared that the presence of 10% infected synoviocytes resulted in the killing of more than 85% of the synoviocytes, demonstrating a substantial bystander effect. Intraarticular injection of Ad.TK in the knees of rhesus monkeys with arthritis, followed by treatment with ganciclovir for 14 days, resulted in increased apoptotic cell death in the synovium of Ad.TK-injected as compared with noninjected joints and ablation of the synovial lining layer. The procedure revealed no toxic side effects. These data suggest that nonsurgical synovectomy by tK gene therapy is feasible.

Adeno-associated virus-mediated delivery of IL-4 prevents collagen-induced arthritis

“…Therefore, immunogenic reactions, elicited by large amounts of empty virus particles or other contaminants, could be less than favorable. Although promising results have been obtained using adenoviral vectors in various arthritis models, 30,32,[49][50][51][52] adenoviral vectors were often associated with loss of gene expression due to significant immunity directed against viral proteins. Furthermore, in contrast to adenoviral vectors expressing LacZ, AAV vectors did not induce humoral or cellular immune responses against the LacZ transgene.…”

Gene therapy for arthritis

“…Positive results were also obtained using a first-generation adenovirus to deliver the herpes thymidine kinase gene to the finger joints of monkeys with collageninduced arthritis. 49 A variety of apoptotic genes that do not require a prodrug such as ganciclovir have also shown good results in animal models. These include FasL, 50,51 TRAIL, 52 and p53.…”

Application des techniques de thérapie génique aux maladies ostéo-articulaires

“…< de protéines apoptotiques, notamment, constitue une stratégie thérapeutique intéressante. Ainsi, le transfert intra-articulaire du gène de la thymidine kinase, dont le produit phosphoryle le ganciclovir administré par voie veineuse en un inhibiteur de l'ADN polymérase, induit une cytolyse de la membrane synoviale et une diminution du volume de l'articulation dans un modèle d'arthrite induite par antigène chez le lapin [7], ou par le collagène chez le singe [8]. Un autre exemple de synovectomie génétique a été réalisé en utilisant le transfert de Fas ligand (FasL) dans un modèle d'arthrite au collagène chez la souris [9,10].…”