Elimination of rheumatoid synovium in situ by Fas ligand 'gene scalpel™'

Surgical synovectomy to remove the inflammatory synovium, can temporarily ameliorate rheumatoid inflammation and delay the progress of joint destruction. An efficient medically induced programmed cell death (apoptosis) in the RA synovium might play a similar role as synovectomy. Gene transfer of FasL has increased the frequency of apoptotic cells in collagen induced mouse arthritis synovium. In this study, we investigated whether a repeated FasL gene transfer could function as a molecular synovectomy to remove human inflammatory synovial tissue in situ.

RA synovium and cartilage from joint replacement surgeries of 5 patients were cut into small pieces at about 2 × 3 × 3 mm³/piece and then was grafted subcutaneously into male C.B-17 SCID mice aged 6–7 weeks at 0.2 g tissue per mouse. Injections of a recombinant FasL adenovirus into the grafted synovial tissue at the dosage of 10¹¹ particles per mouse were performed twice/month. The control groups were treated with recombinant LacZ adenovirus at the same dosage and time points as Ad-FasL administration.

Compared to the control Ad-LacZ injected RA synovium, the Ad-FasL injected RA-synovium was dramatically reduced in size and weight. After 8 weeks the weights of grafted RA synovium were 0.039 ± 0.024 g in the Ad-FasL treated group and 0.152 ± 0.021 g in the Ad-LacZ treated group (P < 0.01). Both synoviocytes and mononuclear cells were greatly decreased after the 2 months treatment with Ad-FasL.

Our in vivo investigation of gene transfer to human synovium in SCID mice suggests that arresting inflammatory synovium at an early stage of RA by intra-articular gene transfer of an apoptosis inducer, such as FasL, might be possible.