GENE THERAPY FOR RHEUMATOID ARTHRITIS AIMING TELOMERASE AS A TARGET

端粒酶是人类细胞无限增殖所必需的。而它的激活在细胞永生中起着循环作用。滑膜组织中端粒酶活性的检测有助于类风湿关节炎(RA)的诊断。我们还发现RA滑膜组织中的端粒酶活性可能来源于浸润性的单个核细胞，可能参与了RA的发病机制，而RA中四聚酶活性的存在可能是一种侵袭性表型的指标。我们评估了多肽核酸(PNAS)介导的端粒酶活性在不同细胞系中的抑制作用。针对部分端粒酶基因的反义PNA对端粒酶活性的抑制作用不明显，提示细胞摄取可能是一个限制因素。在感染各种人细胞系后，该载体对端粒酶活性没有抑制作用。结果表明，该载体的构建有待进一步研究。此外，构建了表达内源性抗炎介质脂皮素1的腺病毒载体。A549细胞感染该载体后前列腺素E_2产生减少，提示该载体可模拟皮质类固醇的部分作用。应继续进一步探索新的治疗策略。

Telomerase is essential for the indefinite proliferation of human cells. And its activation plays a circle role in cellular immortality. We have shown that detection of telomerase activity in synovial tissues is useful for diagnosis of rheumatoid arthritis (RA). We also have shown that telomerase activity in RA synovial tissue is likely derived from infiltrating mononuclear cells and may be involved in the pathogenesis of RA and that the presence of tetomerase activity in RA may be an indicator of an aggressive phenotype.We evaluated peptide nucleic acids, (PNAS) - mediated inhibition of telomerase activity in various cell lines. The antisense PNAS against a part of telomerase gene demonstrated little inhibitory effect on telomerase activity, indicating that cellular uptake might be a limiting factor.Next, an adenovirus vector expressing antisense mRNA against a part of telomerase gene was constructed. Telomerase activities in various human cell lines infected with ,the vector were not inhibited. The result indicate that the construct of the vector needs to be further investigated.Further, an adenovirus vector expressing lipocortin 1, an endogenous anti-inflammation mediator, was constructed. A549 cells infected with the vector showed reduced prostaglandin E2 production, which indicate the vector could mimic a part of actions of corticosteroid. Further exploration for new therapeutic strategy should be continued.