Abstract 483: Prevention of Aneurysm Formation using Ribbon-type Decoy Oligodeoxynucleotides against NFκB and Ets in a Rat Model

Abstract

Current therapy to treat abdominal aortic aneurysm (AAA) is limited to elective surgical repair. Especially, there is no well-defined treatment strategy for small AAAs. Therefore, the development of a novel therapeutic approach to treat AAA is awaited. We focused on the simultaneous inhibition of the transcription factors, NFκB and ets. Indeed, we previously reported the preventive and regressive effects of chimeric decoy oligodeoxynucleotides (ODN) against NFκB and ets. However, local application of ODN is necessary due to easily degradation. To overcome this limitation, we developed novel chimeric decoy ODN with a ribbon-shaped circular structure (ribbon-type chimeric decoy ODN, RC-ODN) to stabilize decoy ODN against nucleases. First, we examined the stability of RC-ODN. RC-ODN was more stable than the conventional phosphorothioated chimeric decoy ODN (PC-ODN) after incubation in the presence of exonuclease or serum. In addition, the inhibitory effect of RC-ODN on MMP-9 expression in cultured THP-1 cells was more potent than that of PC-ODN (n=8, P<0.005). To achieve a minimally invasive molecular therapy, intra-peritoneal application of RC-ODN was performed in a rat AAA model. One week after injection of FITC-labeled RC-ODN, FITC-positive macrophages, migrated from peritoneal space, could be detected in the aneurismal wall. In addition, EMSA showed that both NFκB and ets activity were inhibited by RC-ODN. 4 weeks after treatment, transfection of RC-ODN inhibited the aortic dilatation as compared to control or ribbon-type scrambled decoy ODN transfer (n=6 per group, RC-ODN 5.66±1.08 mm 2 , Scrambled 13.89±3.55 mm 2 , P<0.05). Interestingly, a significant preservation of elastic fibers was observed with RC-ODN treatment, accompanied by a reduction of MMP-9 activity (P<0.0005) and MMP-12 expression (P<0.0005), while the recruitment of macrophages was not inhibited. The expression of cysteine proteases, cathepsin B and K, was also suppressed by RC-ODN treatment (P<0.05). Here, the present study provided a novel strategy to treat AAA by the simultaneous inhibition of NFκB and ets using intra-peritoneal application of RC-ODN in a rat model. Minimally invasive molecular therapy using this strategy is expected to be useful for treating AAA.