Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model

Abstract

The data show that cytokines can be successfully inserted into the genome of human RA synovial fibroblasts using a retroviral vector delivery system, and that the SCID mouse model of human RA is a valuable tool for examining the effects of gene transfer. In addition, inhibition of more than one cytokine pathway may be required to inhibit both synovial- and chondrocyte-mediated cartilage destruction in RA.

Gene therapy for arthritis

“…However, they have limitations 95 as many studies have used prophylactic interventions instead of treatment after disease onset, some models are short term (5-10 days) and do not reflect the long-term chronic nature of the human disease. Yet, some studies have been carried out for a few weeks post disease onset in rodents, 10,41 in xenotransplantation models of arthritis using human synoviocytes and cartilage, 96 in large animals such as horses, 39 and in a monkey CIA model. 43 It will be important to investigate the effects of gene therapy for long-term arthritis in chronic and spontaneous transgenic models of disease that can help elucidate and define new therapeutic targets, novel methods of delivery as well as possible systemic side effects.…”

Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

“…35,2 Fresh articular cartilage of the knee was obtained from the pathology department and cut into 2-3 mm 3 pieces. Under sterile conditions, the sponges containing the transduced fibroblasts were coimplanted with the cartilage pieces under the renal capsule in the SCID mice.…”

“…The invasion scores was decribed previously. 35 Of every co-implant, the invasion scores were determined by taking the means of the sections with the highest score. Per group the means 7 s.e.m.…”

Gene Therapy of Arthritis.

“…It inhibited strikingly the invasion of human cartilage by human rheumatoid synovial fibroblasts, but had no ability to prevent the clearing of matrix from around the chondrocytes. Transfer of a bivalent TNFsRgene was without consistent affect on either parthway of cartilage breakdown (33).…”

“…Retroviral transfer of an IL-IRa CDNAto human, rheumatoid synovial fibroblasts failed to inhibit their ability to invade cartilage directly but in agreement with the rabbit data, strongly suppressed chondrocyte-mediated chondrolysis (32). Transfer of the VIL-10 gene had the opposite effect (33). It inhibited strikingly the invasion of human cartilage by human rheumatoid synovial fibroblasts, but had no ability to prevent the clearing of matrix from around the chondrocytes.…”