Novel molecular targeting of Necl 5 to prevent intimal hyperplasia and restenosis

S OF THE YEAR Plenary Session IR Debates: Controversies and Opportunities Wednesday, March 26, 2014 10:00 AM – 11:30 AM Room: 6A/B 10:00 AM Abstract No. 1 24-month final results from the renova study: a randomized controlled comparison of stent grafts and balloon angioplasty for dialysis access graft preservation Z. Haskal; Radiology and Medical Imaging, Univ of Virginia, Charlottesville, VA Purpose: To present the final, long-term data from the randomized comparison of an ePTFE stent graft (Flairs, Bard Peripheral Vascular) vs. balloon angioplasty (PTA) for treatment of A-V graft stenoses. Materials and Methods: A 28-site prospective controlled U. S. study enrolled 270 patients with malfunctioning upper extremity arteriovenous grafts with graft-vein anastomotic stenoses of Z 50%: 132 patients received PTA and 138 received stent-grafts (SG). Demographic data were similar (po 0.05). Follow-up imaging and intervention were event-driven, i.e. access dysfunction associated with clinical or hemodynamic abnormalities. 24 month outcome measures included: treatment area primary patency (TAPP), overall access circuit primary patency (ACPP), and index of patency function (IPF, # mos/ # interventions). Results: 191 patients completed the study (97 SG patients; 94 PTA patients). Five patients were lost to follow-up or withdrew; 74 patients died during the study (36, PTA group; 38, SG). At 12 months, SG TAPP and ACPP were significantly better than PTA alone (po0.007). SG results remained significantly better at 24 months: SG TAPP was 26.9%, vs. 13.5% for PTA (po0.001); SG ACPP was 9.5% vs. 5.5% respectively (p1⁄40.01), SG IPF was 7.1 7.0 mos/intervention compared to 5.3 5.2 for PTA. The number of access circuit re-interventions before graft abandonment was 4.3 for the PTA group compared to 3.4 for the SG group. There were no significant differences in per-patient number nor type of adverse events rates among the groups, including infection, pseudoaneurysm, or thrombotic occlusion (36.4% PTA group, 43.5% SG group, p1⁄40.26). Access circuit stenosis warranting Underline indicates that the author is the presenter. intervention occurred significantly more often in the PTA (82.6%) vs. the SG group (63.0%, po0.001). Conclusion: At the 2 year conclusion of the RENOVA trial, stent grafts proved as safe as balloon angioplasty and more effective. They provided a two-fold sustained advantage over balloon angioplasty in treatment area and overall access patency. The need for repeat intervention was less and the time to subsequent intervention was longer in the stent graft patients. 10:12 AM Abstract No. 2 Novel molecular targeting of Necl 5 to prevent intimal hyperplasia and restenosis M. Naeem, R. Abid, T. Murphy, W.K. Park, D.R. Mills; Vascular and Interventional Radiology/ Vascular Disease Research Center, Rhode Island Hospital / Warren Alpert Medical School, Brown University, Providence, RI; Molecular Imaging/ Diagnostic Imaging, Rhode Island Hospital / Warren Alpert Medical School, Brown University, Providence, RI; Cardiothoracic Surgery, Rhode Island Hospital / Warren Alpert Medical School, Brown University, Providence, RI; Hematology and Oncology, Rhode Island Hospital / Warren Alpert Medical School, Brown University, Providence, RI Purpose: Intimal hyperplasia (IH) is implicated in the pathogenesis of restenosis and is the main reason for treatment failure after revascularization procedures. One example of a strategy to reduce restenosis is the use of anti-inflammatory drugs such as paclitaxel, usually administered as a coating on a stent. Recently, the cell surface receptor Necl-5/CD-155 has been reported to be involved in VSMC proliferation and migration in vitro, and in VSMC de-differentiation and neointimal hyperplasia in vivo. Our aim was to see whether molecular targeting of Necl-5 using monoclonal antibody (MAb) can inhibit vascular smooth muscle proliferation in vitro. Materials and Methods: We developed anti-rat Necl-5 MAb and a novel ferritin conjugate containing the mAb. In order to assess specificity of its activity, we used silencer RNA (si-RNA) (in regenerating liver cells) and magnetic resonance imaging (MRI) techniques (in Necl-5 expressing tumor grafts). Then, we grew rat vascular smooth muscle cells (Lonza) in a 24-well plates and serum-starved for 24 hrs, prior to addition of PDGF-BB (10 ng/ml) with and without MAb (50 ng/ml) for 20 hrs. The experiment was performed by standard MTT assay protocol. Results: MAb targeted Necl-5 on regenerating liver cells and xenograft tumor cells in mice with high specificity, and the MAb-ferritin nanoconjugate exhibited strong magnetic resonance imaging (MRI) contrast characteristics. Nanoconjugate targeted tumor showed significant reduction of T2 signals at 4 hours (43.6 9.9 seconds) as compared to initial baseline value (72.8 11 seconds), whereas similar results were not observed in JVIR ’ Abstracts of the Year S7 the control animal between baseline (62.8 8.3 seconds) and 4 hours (73.6 9.1 seconds). The MTT assay of rat vascular smooth muscle cells showed that MAb inhibited PDGFinduced rat aortic VSMC proliferation by 21 3.2% compared to control nonspecific immunoglobulin-G. Conclusion: Anti-Necl 5 antibody is very specific for rat Necl5 surface receptor, and results in decreased rat vascular smooth muscle proliferation. This represents a potential new molecular target to prevent restenosis after vascular intervention.