The development of molecular therapy using decoy oligonucleotides : for clinical applications.

本研究开发了一种新的调控两种转录因子活性的嵌合诱饵策略，并评估了基于动脉粥样硬化的心血管疾病新分子治疗的可能性。1）腹主动脉瘤（AAA）是一种常见的与衰老和动脉粥样硬化相关的退行性疾病。为了开发一种新的治疗方法，我们研究了在兔AAA模型中调节炎症和基质降解的转录因子NF κ B和ets的同时抑制。超声和血管造影分析表明，嵌合诱饵寡脱氧核苷酸治疗显着阻止弹性蛋白酶诱导的主动脉扩张的进展。嵌合诱饵寡核苷酸的转染降低MMP-2和MMP-9的活性相比，乱诱饵寡核苷酸。治疗与嵌合诱饵寡脱氧核苷酸显着抑制蛋白水解的弹性蛋白相比， ...更多信息 乱序诱饵寡脱氧核苷酸。有趣的是，免疫组化研究表明，主要是外膜和中膜的巨噬细胞浸润显着抑制转染嵌合诱饵寡核苷酸。2）虽然自体静脉仍然是旁路移植物的常用管道，新生内膜增生是已知的静脉移植失败的主要疾病过程之一。我们研究了NF κ B诱骗寡脱氧核苷酸（ODN）对预防兔高胆固醇血症模型静脉移植失败的抑制作用。静脉植入后4周，用NFkB诱饵ODN治疗显著抑制内膜增生。NFkB decoy ODN可显著抑制巨噬细胞的募集和血管平滑肌细胞（VSMC）的增殖，并显著增加VSMC的凋亡。转染E2 F和NFkB嵌合诱饵ODN后，吻合口内膜增生明显减少。免疫组织化学染色显示，嵌合诱饵ODN抑制巨噬细胞的DNA合成和迁移，随后抑制炎症变化。这些发现提出了预防移植失败的新策略的可能性。少

In this program, we developed a newly system, chimeric decoy strategy which regulate the activity of two transcription factors, and evaluated the possibility of novel molecular therapies for cardiovascular diseases based on atherosclerosis.1) Abdominal aortic aneurysm (AAA) is a common degenerative condition associated with aging and atherosclerosis. To develop a novel therapeutic approach, we examined the simultaneous inhibition of the transcription factors NFkB and ets, which regulate inflammation and matrix degradation, in a rabbit AAA model. Ultrasound and angiographic analysis demonstrated that treatment with chimeric decoy oligodeoxynucleotides significantly prevented the progression of elastase-induced aortic dilatation. Transfection of chimeric decoy oligodeoxynucleotides reduced the activities of MMP-2 and MMP-9 as compared to scrambled decoy oligodeoxynucleotides. Treatment with chimeric decoy oligodeoxynucleotides markedly inhibited the proteolysis of elastin as compared to … More scrambled decoy oligodeoxynucleotides. Interestingly, immunohistochemical study demonstrated that macrophage infiltration of mainly the adventitia and media was significantly inhibited by transfection of chimeric decoy oligodeoxynucleotides.2) Although autologous vein remains the commonly used conduit for bypass grafts, neointimal hyperplasia is known to be one of the major disease processes in vein graft failure. We investigated the inhibitory effect of NFkB decoy oligodeoxynucleotides (ODN) on prevention of vein graft failure in a rabbit hypercholesterolemic model. Four weeks after vein implantation, the treatment with NFkB decoy ODN significantly suppressed intimal hyperplasia. Treatment of NFkB decoy ODN significantly inhibited the recruitment of macrophages and the proliferation of vascular smooth muscle cells (VSMC), while the apoptosis in VSMC was significantly increased by NFkB decoy ODN. Moreover, transfection of chimeric decoy ODN against E2F and NFkB resulted in significantly inhibition of anastomotic intimal hyperplasia. Immunohistochemical staining revealed that chimera decoy ODN inhibited DNA synthesis and the migration of macrophages, followed by the inhibition of inflammatory changes. These findings raised the possibility of novel strategy for prevention of graft failure. Less