Amelioration of experimental arthritis by a telomerase-dependent conditionally replicating adenovirus that targets synovial fibroblasts.
OBJECTIVE
Synovial fibroblasts (SFs) play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). It has been documented that the phenotype of rheumatoid synovium is similar, in many respects, to that of an aggressive tumor. In this study, a novel, genetically engineered adenovirus was designed to lyse SFs that exhibit high telomerase activity and p53 mutations, and its effects as a novel therapeutic strategy were assessed in an experimental arthritis model.


METHODS
An E1B-55-kd-deleted adenovirus driven by the human telomerase reverse transcriptase promoter was constructed (designated Ad.GS1). Cytolysis of SFs and productive replication of Ad.GS1 in the SFs of rats with collagen-induced arthritis (CIA), as well as the SFs of patients with RA (RASFs), were assessed in vitro and in vivo. Treatment responses, as well as the presence of disease-related cytokines and enzymes in the ankle joints, were determined in the murine model.


RESULTS
Ad.GS1 replicated in and induced cytolysis of human RASFs and SFs from arthritic rats, but spared normal fibroblasts. Bioluminescence imaging in vivo also demonstrated replication of Ad.GS1 in arthritic rat joints, but not in normal rat joints. Intraarticular administration of Ad.GS1 significantly reduced the ankle circumference, articular index scores, radiographic scores, and histologic scores and decreased the production of interleukin-1beta, matrix metalloproteinase 9, and prolyl 4-hydroxylase in rats with CIA compared with their control counterparts.


CONCLUSIONS
This study is the first to demonstrate the amelioration of arthritic symptoms by a novel, telomerase-dependent adenovirus in the rat CIA model, an experimental model that resembles human RA. In addition, the results suggest that because of its ability to induce cytolysis of SFs, this virus may be further explored as a therapeutic agent in patients with RA.
Chen
Shih-Yao
SY
National Cheng Kung University Medical College, Tainan, Taiwan.
Shiau
Ai-Li
AL
Shieh
Gia-Shing
GS
Su
Chih-Hau
CH
Lee
Che-Hsin
CH
Lee
Hwei-Ling
HL
Wang
Chrong-Reen
CR
Wu
Chao-Liang
CL
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002460:Cell Line; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011991:Receptors, Virus / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
D017501:Adenovirus E1B Proteins; D053583:Interleukin-1beta; D011991:Receptors, Virus; C085301:adenovirus receptor; D011393:Procollagen-Proline Dioxygenase; C509186:TERT protein, human; D019098:Telomerase; D020780:Matrix Metalloproteinase 9