Small-Molecule Inhibitors to Prevent Intimal Hyperplasia after Balloon Angioplasty and Lower Extremity Bypass

INTRODUCTION: Interventions for limb salvage and cardiac reperfusion fail due to restenosis caused by intimal hyperplasia (IH). To address this, we explored the ability of Amlexanox (AML), an inhibitor of TBK1/IKKε and modulator of atherogenic IFNγ signaling to prevent IH in two animal models. METHODS: Rats were injected IP with AML (100 mg/kg/day) or control 7 days (D) before, and up to harvest at 14D after carotid artery angioplasty. Canines were treated with oral AML (30 mg/kg/day) or control 7D prior to cephalic vein to common femoral artery bypass, and up to harvest at 42D. All vessels were H&E-stained to measure Intima:Media (I/M) ratios, and CD31 IHC to assess re-endothelialization. RESULTS: We validated in vitro AML as an inhibitor of TBK1/IKKε activation and downstream IFNγ/STAT1 signaling in human endothelial and smooth muscle cells. In vivo, systemic administration of AML significantly decreased IH following rat carotid balloon angioplasty. I/M ratios at 14D were 0.43 ± 0.54 and 1.38 ± 0.71 in AML vs control vessels (Fig 1A; p < .001, n = 7-8). This benefit corresponded with accelerated reendothelialization in AML vs control vessels, as evidenced by CD31 IHC. Remarkably, this effect of AML was reproduced with oral administration in a clinically relevant canine weight-bearing venous bypass graft (Fig. 1B; n = 2). Systemic AML showed no evidence of toxicity.Figure 1CONCLUSION: Our data are first to report that systemic use of AML is well-tolerated, prevents IH after carotid angioplasty and limits pathologic vascular remodeling following lower extremity bypass. Future studies are focused on incorporating AML to stents and balloons for local/extended delivery.